Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_1866.6
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_2741.1
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112374
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#SmallMolecule5
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_27630.1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1639
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112594
FUNCTION: Plays a key role in the control of the eukaryotic cell cycle. It is required in higher cells for entry into S-phase and mitosis. p34 is a component of the kinase complex that phosphorylates the repetitive C-terminus of RNA polymerase II. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. CATALYTIC ACTIVITY: ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate. ENZYME REGULATION: Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-161 activates it. SUBUNIT: Forms a stable but non-covalent complex with a regulatory subunit and with a cyclin. Interacts with DLGAP5. Isoform 2 is unable to complex with cyclin B1 and also fails to bind to the CDK inhibitor p21. Interacts with catalytically active CCNB1 and RALBP1 during mitosis to form an endocytotic complex during interphase. SUBCELLULAR LOCATION: Nucleus (By similarity). ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=P06493-1; Sequence=Displayed; Name=2; Synonyms=CDC2deltaT; IsoId=P06493-2; Sequence=VSP_021375; TISSUE SPECIFICITY: Isoform 2 is found in breast cancer tissues. SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdc2/"; GENE SYNONYMS: CDC2. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112596
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112598
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#SmallMolecule6
14-3-3 protein beta/alpha, N-terminally processed
FUNCTION: Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathway. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. SUBUNIT: Homodimer. Interacts with SSH1 and TORC2/CRTC2. Interacts with ABL1; the interaction results in cytoplasmic location of ABL1 and inhition of cABL-mediated apoptosis. Interacts with ROR2 (dimer); the interaction results in phosphorylation of YWHAB on tyrosine residues. Interacts with GAB2 and YAP1 (phosphorylated form). SUBCELLULAR LOCATION: Cytoplasm. Melanosome. Note=Identified by mass spectrometry in melanosome fractions from stage I to stage IV. ALTERNATIVE PRODUCTS: Event=Alternative initiation; Named isoforms=2; Name=Long; IsoId=P31946-1; Sequence=Displayed; Name=Short; IsoId=P31946-2; Sequence=VSP_018632; Note=Acetylated on Met-1 (By similarity); PTM: The alpha, brain-specific form differs from the beta form in being phosphorylated (By similarity). PTM: Isoform Short contains a N-acetylmethionine at position 1 (By similarity). SIMILARITY: Belongs to the 14-3-3 family. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_5391.2
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_2607.1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex1116
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=447100
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1067638
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein2357
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112398
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#BiochemicalReaction703
Authored: Charalambous, M, 2005-02-04 06:50:22
MEK2 dissociates from phospho-ERK2, allowing phospho-ERK2 to dimerise with another phospho-ERK2.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep897
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_2275.1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex679
Microtubule- associated protein-2 kinase
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1632
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_143.6
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=48888
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=62725
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep1231
FUNCTION: Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig- secreting cells Involved in lymphocyte and monocyte differentiation. It induces myeloma and plasmacytoma growth and induces nerve cells differentiation Acts on B-cells, T-cells, hepatocytes, hematopoeitic progenitor cells and cells of the CNS. Also acts as a myokine. It is discharged into the bloodstream after muscle contraction and acts to increase the breakdown of fats and to improve insulin resistance. SUBCELLULAR LOCATION: Secreted. PTM: N- and O-glycosylated. POLYMORPHISM: Genetic variations in IL6 may be correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disrutption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture. DISEASE: Genetic variations in IL6 are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302]. An inflammatory articular disorder with systemic- onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. DISEASE: Note=A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men. SIMILARITY: Belongs to the IL-6 superfamily. WEB RESOURCE: Name=R&D Systems' cytokine mini-reviews: IL-6; URL="http://www.rndsystems.com/molecule_detail.aspx?m=1648"; WEB RESOURCE: Name=Wikipedia; Note=Interleukin-6 entry; URL="http://en.wikipedia.org/wiki/Interleukin_6"; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/il6/"; WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=IL6"; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/IL6ID519ch7p15.html"; GENE SYNONYMS: IFNB2. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112563
Interleukin-6 receptor subunit alpha long transmembrane form
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1636
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep887
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_3571.1
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1067661
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_3932.1
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_3339.1
Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1633
At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'MEK1' are present. At the end of this reaction, 1 molecule of 'phospho_MEK1', and 2 molecules of 'ADP' are present. This reaction takes place in the 'cytosol' and is mediated by the 'protein serine/threonine kinase activity' of 'phospho-Cdc2 (Thr 161)'.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#BiochemicalReaction695
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112580
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112585
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112584
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_3199.1
Two phospho-ERK1 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#BiochemicalReaction699
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_4906.3
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep888
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1067672
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Pathway270
MEK is phosphorylated and activated by RAF.
Authored: Charalambous, M, 2004-04-29 09:21:24
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_27429.1
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_1482.4
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#SmallMolecule84
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein2356
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112570
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_4992.1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep894
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_3906.1
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_4863.1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Catalysis485
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1067687
Tyrosine phosphorylated Interleukin-6 receptor subunit beta long transmembrane form
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1641
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1638
The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_27564.1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1637
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_634.5
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_2822.1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein2355
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_2196.5
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1624
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_5485.2
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_2640.2
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex1117
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=59504
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=59502
Dual specificity mitogen-activated protein kinase kinase 2
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1643
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162573
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex681
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112411
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1112543
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_4782.1
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29438
RAF proto-oncogene serine/threonine-protein kinase
FUNCTION: Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Part of the Ras-dependent signaling pathway from receptors to the nucleus. Protects cells from apoptosis mediated by STK3. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. COFACTOR: Binds 2 zinc ions per subunit. SUBUNIT: Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC). Interacts with Ras proteins; the interaction is antagonized by RIN1. Weakly interacts with RIT1 (By similarity). Interacts with STK3; the interaction inhibits its pro-apoptotic activity. Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr- 232'). ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; Synonyms=6C; IsoId=P04049-1; Sequence=Displayed; Name=2; Synonyms=1A; IsoId=P04049-2; Sequence=VSP_034649; TISSUE SPECIFICITY: In skeletal muscle, isoform 1 is more abundant than isoform 2. PTM: Phosphorylated upon DNA damage, probably by ATM or ATR. Phosphorylation at Thr-269 increases its kinase activity. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. DISEASE: Defects in RAF1 are the cause of Noonan syndrome type 5 (NS5) [MIM:611553]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. DISEASE: Defects in RAF1 are the cause of LEOPARD syndrome type 2 (LEOPARD2) [MIM:611554]. LEOPARD syndrome is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness. SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily. SIMILARITY: Contains 1 phorbol-ester/DAG-type zinc finger. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 RBD (Ras-binding) domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RAF1"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/raf1/"; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/RAF1ID42032ch3p25.html"; GENE SYNONYMS: RAF. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex691
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex692
Dual specificity mitogen-activated protein kinase kinase 1 (EC 2.7.1.-) (MAP kinase kinase 1) (MAPKK 1) (ERK activator kinase 1) (MAPK/ERK kinase 1) (MEK1)
Dual specificity mitogen-activated protein kinase kinase 1
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1629
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep886
Tyrosine-protein phosphatase non-receptor type 11
FUNCTION: Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. CATALYTIC ACTIVITY: Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate. SUBUNIT: Interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1 (By similarity). Interacts with MCA32 (tyrosine-phosphorylated) (By similarity). Interacts with PTPNS1 and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts with FCRL3, FCRL4, FCRL6 and ANKHD1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts with GAB2. Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1. SUBCELLULAR LOCATION: Cytoplasm. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=3; Name=1; Synonyms=PTP2Ci; IsoId=Q06124-1; Sequence=Displayed; Name=2; Synonyms=PTP2C; IsoId=Q06124-2; Sequence=VSP_016672; Name=3; IsoId=Q06124-3; Sequence=VSP_016672, VSP_016673, VSP_016674; TISSUE SPECIFICITY: Widely expressed, with highest levels in heart, brain, and skeletal muscle. DOMAIN: The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme. PTM: Phosphorylated on Tyr-546 and Tyr-584 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. DISEASE: Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:151100]. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness. DISEASE: Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:163950]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Note=Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant. DISEASE: Defects in PTPN11 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte- macrophage colony stimulating factor. DISEASE: Defects in PTPN11 are a cause of metachondromatosis (MC) [MIM:156250]. It is a skeletal disorder with radiologic fetarures of both multiple exostoses and Ollier disease, characterized by the presence of multiple enchondromas and osteochondroma-like lesions. SIMILARITY: Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily. SIMILARITY: Contains 2 SH2 domains. SIMILARITY: Contains 1 tyrosine-protein phosphatase domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/PTPN11ID41910ch12q24.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PTPN11"; GENE SYNONYMS: PTP2C SHPTP2. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1635
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Catalysis486
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=62719
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112339
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=62717
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_1836.2
FUNCTION: Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. FUNCTION: Low concentration of a soluble form of IL6 receptor acts as an agonist of IL6 activity. SUBUNIT: Hexamer of two molecules each of IL6, IL6R and IL6ST. SUBCELLULAR LOCATION: Isoform 1: Basolateral cell membrane; Single-pass type I membrane protein. SUBCELLULAR LOCATION: Isoform 2: Secreted. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; Synonyms=Long; IsoId=P08887-1; Sequence=Displayed; Name=2; Synonyms=Short; IsoId=P08887-2; Sequence=VSP_001682, VSP_001683; TISSUE SPECIFICITY: Isoform 2 is expressed in peripheral blood mononuclear cells and weakly found in urine and serum. DOMAIN: The two fibronectin type-III-like domains, contained in the N-terminal part, form together a cytokine-binding domain. DOMAIN: The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell- surface receptor binding. PTM: A short soluble form may also be released from the membrane by proteolysis. SIMILARITY: Belongs to the type I cytokine receptor family. Type 3 subfamily. SIMILARITY: Contains 1 fibronectin type-III domain. SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like) domain. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112336
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex686
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_962.4
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_2875.1
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Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active.
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Authored: Charalambous, M, 2005-01-07 11:17:43
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Mitogen-activated protein kinase 1 (EC 2.7.1.-) (Extracellular signal- regulated kinase 2) (ERK-2) (Mitogen-activated protein kinase 2) (MAP kinase 2) (MAPK 2) (p42-MAPK) (ERT1)
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Activated MEK phosphorylates and activates ERK.
Mitogen-activated protein kinase 3 (EC 2.7.1.-) (Extracellular signal- regulated kinase 1) (ERK-1) (Insulin-stimulated MAP2 kinase) (MAP kinase 1) (MAPK 1) (p44-ERK1) (ERT2) (p44-MAPK) (Microtubule- associated protein-2 kinase)
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FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. ENZYME REGULATION: Alternate between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase- activating protein (GAP). SUBUNIT: In its GTP-bound form interacts with PLCE1. Interacts with TBC1D10C. Interacts with RGL3. Interacts with HSPD1 (By similarity). Forms a signaling complex with RASGRP1 and DGKZ. Interacts with RASSF5. Interacts with HRAS. SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side. Golgi apparatus membrane; Lipid-anchor. Note=Shuttles between the plasma membrane and the Golgi apparatus. PTM: Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi. PTM: S-nitrosylated; critical for redox regulation. Important for stimulating guanine nucleotide exchange. No structural perturbation on nitrosylation. MASS SPECTROMETRY: Mass=6223; Mass_error=2; Method=Electrospray; Range=112-166; Source=PubMed:9020151; MASS SPECTROMETRY: Mass=6253; Mass_error=2; Method=Electrospray; Range=112-166; Note=Includes one nitric oxide molecule; Source=PubMed:9020151; DISEASE: Defects in HRAS are the cause of Costello syndrome (COSTS) [MIM:218040]; also known as faciocutaneoskeletal syndrome. Costello syndrome is a rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities. DISEASE: Defects in HRAS are the cause of congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040]. CMEMS is a variant of Costello syndrome. DISEASE: Defects in HRAS may be a cause of susceptibility to Hurthle cell thyroid carcinoma (HCTC) [MIM:607464]. Hurthle cell thyroid carcinoma accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms. DISEASE: Note=Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors. DISEASE: Defects in HRAS are a cause of susceptibility to bladder cancer (BLC) [MIM:109800]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. DISEASE: Note=Defects in HRAS are the cause of oral squamous cell carcinoma (OSCC). SIMILARITY: Belongs to the small GTPase superfamily. Ras family. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/HRASID108.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HRAS"; GENE SYNONYMS: HRAS1. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. ENZYME REGULATION: Alternate between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase- activating protein (GAP). SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side. Golgi apparatus membrane; Lipid-anchor. Note=Shuttles between the plasma membrane and the Golgi apparatus. PTM: Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi. DISEASE: Defects in NRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. DISEASE: Defects in NRAS are the cause of Noonan syndrome type 6 (NS6) [MIM:613224]. A syndrome characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits. MISCELLANEOUS: Mutations which change AA 12, 13 or 61 activate the potential of Ras to transform cultured cells and are implicated in a variety of human tumors. SIMILARITY: Belongs to the small GTPase superfamily. Ras family. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/NRASID92.html"; WEB RESOURCE: Name=NRASbase; Note=NRAS mutation db; URL="http://bioinf.uta.fi/NRASbase/"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/nras/"; WEB RESOURCE: Name=Wikipedia; Note=RAS proteins entry; URL="http://en.wikipedia.org/wiki/RAS_proteins"; GENE SYNONYMS: HRAS1. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. ENZYME REGULATION: Alternate between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase- activating protein (GAP). SUBUNIT: Interacts with PHLPP (By similarity). SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Comment=Isoforms differ in the C-terminal region which is encoded by two alternative exons (IVA and IVB); Name=2A; IsoId=P01116-1; Sequence=Displayed; Name=2B; IsoId=P01116-2, P01118-1; Sequence=VSP_011140, VSP_011141; Note=Variant in position: 153:D->V (in CFC syndrome and NS3), exhibits only minor alterations in its in vitro biochemical behavior compared to wild-type protein. Variant in position: 156: F->I (in NS3/CFC syndrome). Variant in position: 156: F->L (found in a patient with Costello syndrome), exhibits an increase in intrinsic and guanine nucleotide exchange factor catalyzed nucleotide exchange in combination with an impaired GTPase-activating protein-stimulated GTP hydrolysis but functional in interaction with effectors; DISEASE: Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. DISEASE: Defects in KRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte- macrophage colony stimulating factor. DISEASE: Defects in KRAS are the cause of Noonan syndrome type 3 (NS3) [MIM:609942]. Noonan syndrome (NS) [MIM:163950] is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS3 inheritance is autosomal dominant. DISEASE: Defects in KRAS are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio- cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. DISEASE: Note=KRAS mutations are involved in cancer development. SIMILARITY: Belongs to the small GTPase superfamily. Ras family. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/KRASID91.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KRAS"; WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=KRAS"; GENE SYNONYMS: KRAS2 RASK2. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
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MEK1 phosphorylates the critical Tyrosine and Threonine on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity.
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FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. SUBUNIT: Interacts with MORG1 (By similarity). PTM: MAPKK is itself dependent on Ser/Thr phosphorylation for activity catalyzed by MAP kinase kinase kinases (RAF or MEKK1). PTM: Acetylation of Ser-222 and Ser-226 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway. DISEASE: Defects in MAP2K2 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio- cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MAP2K2"; GENE SYNONYMS: MEK2 MKK2 PRKMK2. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
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MEK1 dissociates from phospho-ERK1, allowing phospho-ERK1 to dimerise with another phospho-ERK1.
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FUNCTION: Signal-transducing molecule. The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize gp130 for initiating signal transmission. Binds to IL6/IL6R (alpha chain) complex, resulting in the formation of high-affinity IL6 binding sites, and transduces the signal. Does not bind IL6. May have a role in embryonic development (By similarity). The type I OSM receptor is capable of transducing OSM-specific signaling events. SUBUNIT: Interacts with INPP5D/SHIP1 (By similarity). Forms heterodimers composed of LIPR and IL6ST (type I OSM receptor). Also forms heterodimers composed of OSMR and IL6ST (type II OSM receptor). Homodimer. The homodimer binds two molecules of herpes virus IL6. Component of a hexamer of two molecules each of IL6, IL6R and IL6ST. SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I membrane protein. SUBCELLULAR LOCATION: Isoform 2: Secreted. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=P40189-1; Sequence=Displayed; Name=2; Synonyms=GP130-RAPS; IsoId=P40189-2; Sequence=VSP_001684, VSP_001685; TISSUE SPECIFICITY: Found in all the tissues and cell lines examined. Expression not restricted to IL6 responsive cells. INDUCTION: Leukemia inhibitory factor (LIF) and Oncostatin-M (OSM) activate the type I OSM receptor while only OSM can activate the type II OSM receptor. DOMAIN: The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell- surface receptor binding. DOMAIN: The box 1 motif is required for JAK interaction and/or activation. PTM: Phosphorylation of Ser-782 down-regulates cell surface expression. PTM: Heavily N-glycosylated. SIMILARITY: Belongs to the type I cytokine receptor family. Type 2 subfamily. SIMILARITY: Contains 5 fibronectin type-III domains. SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like) domain. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
FUNCTION: Involved in both the initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors such as ELK1. Phosphorylates EIF4EBP1; required for initiation of translation. Phosphorylates microtubule-associated protein 2 (MAP2). Phosphorylates SPZ1 (By similarity). Phosphorylates heat shock factor protein 4 (HSF4) and ARHGEF2. FUNCTION: Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. COFACTOR: Magnesium (By similarity). ENZYME REGULATION: Activated by phosphorylation on tyrosine and threonine in response to insulin and NGF. Both phosphorylations are required for activity (By similarity). SUBUNIT: Interacts with MORG1 (By similarity). Binds to HIV-1 Nef through its SH3 domain. This interaction inhibits its tyrosine- kinase activity. Interacts with its substrates HSF4 and ARHGEF2. Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated form); the interaction, promoted by insulin, leads to nuclear location and MAPK1 activation (By similarity). Interacts with NISCH. Interacts with ARRB2. Interacts with ADAM15. SUBCELLULAR LOCATION: Nucleus. DOMAIN: The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases. PTM: Dually phosphorylated on Thr-185 and Tyr-187, which activates the enzyme. Dephosphorylated by PTPRJ at Tyr-187. SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=CAA77753.1; Type=Erroneous initiation; Note=Translation N-terminally extended; WEB RESOURCE: Name=Wikipedia; Note=Extracellular signal-regulated kinase entry; URL="http://en.wikipedia.org/wiki/Extracellular_signal-regulated_kinase"; GENE SYNONYMS: ERK2 PRKM1 PRKM2. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
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In the cytoplasm activated MEK2 (Serine phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T183) and a critical Tyrosine (Y185).
adenosine 5'-(tetrahydrogen triphosphate)
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'phospho_MEK1 [cytosol]' negatively regulates 'MEK1 phosphorylates ERK-1'
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Activated MEK1 phosphorylates and activates ERK1.
FUNCTION: Involved in both the initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors such as ELK-1. Phosphorylates EIF4EBP1; required for initiation of translation. Phosphorylates microtubule-associated protein 2 (MAP2). Phosphorylates SPZ1 (By similarity). Phosphorylates heat shock factor protein 4 (HSF4). CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. COFACTOR: Magnesium (By similarity). ENZYME REGULATION: Activated by tyrosine phosphorylation in response to insulin and NGF. SUBUNIT: Interacts with MORG1 (By similarity). Binds to HIV-1 Nef. This interaction inhibits its kinase activity. Interacts with HSF4 and NISCH. Interacts with ARRB2. Interacts with ADAM15. DOMAIN: The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases. PTM: Dually phosphorylated on Thr-202 and Tyr-204, which activates the enzyme. Dephosphorylated by PTPRJ at Tyr-204. SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. SIMILARITY: Contains 1 protein kinase domain. GENE SYNONYMS: ERK1 PRKM3. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors
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'IL6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs:p-SHP2 [plasma membrane]' positively regulates 'ERK2 activation'
IL-6-type receptor activation leads to induction of the MAPK cascade. Experiments using gp130 identified that the gp130 SHP2 (SH2-domain-containing tyrosine phosphatase)-binding site Tyr-759 (Stahl et al. 1995) is required for this activation. Mutation of gp130 Tyr-759 impairs IL-6 induced activation of the MAPK cascade (Kim et al. 1998). While there is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway, the molecular details are uncertain. One proposed mechanism suggests SHP2 acts as an adaptor for Grb2-Sos recruitment (Fukada et al. 1996, Kim & Baumann 1999). IL-6 induced SHP2 recruitment to p-Tyr-759 of gp130 was demonstrated but relatively little of the SHP2 remained associated with gp130, suggesting that SHP2 dissociates from the receptor when phosphorylated. This seems inconsistent with a Grb2-Sos recruitment role for SHP2, though it is possible that only low levels or transient recruitment are required. IL-6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of SHP2, whereas an SHP2 mutant missing the Grb2 interaction region significantly suppressed ERK activation. This suggests phosphatase activity is not required for ERK activation while SHP-2 interaction with Grb2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). An alternative proposal suggests that SHP2 and the adaptor protein Gab1 couple gp130 signalling to Erk activation. In this proposal phosphorylated SHP2 dissociates from gp130 and becomes associated with membrane associated Gab1 in a complex with PI3-kinase (Takahashi-Tezuka et al. 1998, Eulenfeld & Schaper 2009). SHP2 interaction is suggested to induce a conformational change in Gab1 that permits Gab1-PI3-kinase activation and enhancement of IL-6-induced Erk pathway activation. However this is speculative, the role of SHP2 phosphatase activity is unclear. Other possible mechanisms are outlined by Dance et al. (2008), extrapolated from growth factor receptor mechanisms but with unknown relevance to IL-6/gp130.
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FUNCTION: Non-receptor tyrosine kinase involved in various processes such as cell cycle progression, apoptosis, mitotic recombination, genetic instability and histone modifications. In the cytoplasm, plays a pivotal role in signal transduction via its association with cytokine receptors, which constitutes an initiating step in signaling for many members of the cytokine receptor superfamily including the receptors for growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), granulocyte-macrophage colony-stimulating factor (CSF2), thrombopoietin (THPO) and multiple interleukins. Following stimulation with erythropoietin (EPO) during erythropoiesis, it is autophosphorylated and activated, leading to its association with erythropoietin receptor (EPOR) and tyrosine phosphorylation of residues in the EPOR cytoplasmic domain. Also involved in promoting the localization of EPOR to the plasma membrane. Also acts downstream of some G-protein coupled receptors. Plays a role in the control of body weight (By similarity). Mediates angiotensin-2-induced ARHGEF1 phosphorylation. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME REGULATION: Regulated by autophosphorylation, can both activate or decrease activity (By similarity). Heme regulates its activity by enhancing the phosphorylation on Tyr-1007 and Tyr- 1008. SUBUNIT: Interacts with EPOR, SIRPA and SH2B1 (By similarity). Interacts with IL23R, SKB1 and STAM2. SUBCELLULAR LOCATION: Endomembrane system; Peripheral membrane protein (By similarity). Nucleus. TISSUE SPECIFICITY: Expressed in blood, bone marrow and lymph node. DOMAIN: Possesses 2 protein kinase domains. The second one probably contains the catalytic domain, while the presence of slight differences suggest a different role for protein kinase 1 (By similarity). PTM: Autophosphorylated, leading to regulate its activity. Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813. Autophosphorylation on Tyr-119 in response to EPO down-regulates its kinase activity. Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are required for maximal kinase activity (By similarity). DISEASE: Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. DISEASE: Defects in JAK2 are a cause of susceptibility to Budd- Chiari syndrome (BCS) [MIM:600880]. It is a syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. DISEASE: Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:263300]. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly. DISEASE: Defects in JAK2 gene may be a cause of essential thrombocythemia (ET) [MIM:187950]. ET is characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications. DISEASE: Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:254450]. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. DISEASE: Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. SIMILARITY: Contains 1 FERM domain. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 SH2 domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/JAK98.html"; COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1626
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Catalysis487
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Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex678
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex693
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex1115
Two phospho-ERK2 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets.
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IL6:sIL6R:Tyrosine phosphorylated IL6RB:Activated JAKs
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex688
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Nuclear translocation of phospho-ERK-2 dimer
Phospho-ERK-2 dimer is translocated from cytosol to nucleoplasm.
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Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep896
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep1415
Dual specificity mitogen-activated protein kinase kinase 2 (EC 2.7.1.-) (MAP kinase kinase 2) (MAPKK 2) (ERK activator kinase 2) (MAPK/ERK kinase 2) (MEK2)
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein2360
A new mechanism for the regulation of Gab1 recruitment to the plasma membrane
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Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1625
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Nuclear translocation of phospho-ERK-1 dimer
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Phospho-ERK-1 dimer is translocated from cytosol to nucleoplasm.
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MEK2 phosphorylates the critical Tyrosine and Threonine on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#BiochemicalReaction702
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex690
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IL-6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex683
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MEK-1/2 have a proline rich domain (P) and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells. MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP.
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guanosine 5'-(tetrahydrogen triphosphate)
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'IL6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs:p-SHP2 [plasma membrane]' positively regulates 'ERK1 activation'
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The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
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Activated MEK2 phosphorylates and activates ERK2.
Tyrosine phosphorylated IL6RB:Activated JAKs
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cPath2-generated. Data version: 20110323, March 23, 2011
cPath2-generated. Data (internal) id: REACTOME_HUMAN
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IL6:Tyrosine phosphorylated trimeric IL-6 receptor:Activated JAKs
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex684
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Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex680
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#PathwayStep893
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Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis
IL6:IL6RA:Tyrosine phosphorylated IL6RB:Activated JAKs
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex685
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Catalysis582
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A purine ribonucleoside 5'-diphosphate having adenine as the nucleobase.
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Non-receptor tyrosine-protein kinase TYK2
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Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of acute-phase plasma protein genes in hepatic cells
In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y).
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FUNCTION: Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. SUBUNIT: Interacts with JAKMIP1. TISSUE SPECIFICITY: Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines. DOMAIN: The FERM domain mediates interaction with JAKMIP1. DISEASE: Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:611521]; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. SIMILARITY: Contains 1 FERM domain. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 SH2 domain. WEB RESOURCE: Name=TYK2base; Note=TYK2 mutation db; URL="http://bioinf.uta.fi/TYK2base/"; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/tyk2/"; COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates ERK1 and ERK2 MAP kinases. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Activated by phosphorylation. SUBUNIT: Interacts with MORG1. Interacts with ARRB2 (By similarity). Interacts with Yersinia yopJ. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; Synonyms=MKK1a; IsoId=Q02750-1; Sequence=Displayed; Name=2; Synonyms=MKK1b; IsoId=Q02750-2; Sequence=VSP_040500; TISSUE SPECIFICITY: Widely expressed, with extremely low levels in brain. PTM: Phosphorylation on Ser/Thr by MAP kinase kinase kinases (RAF or MEKK1) regulates positively the kinase activity. PTM: Acetylation by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway. DISEASE: Defects in MAP2K1 are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio- cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MAP2K1"; GENE SYNONYMS: MEK1 PRKMK1. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
FUNCTION: Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. SUBUNIT: Interacts with IL31RA, IFNAR2, JAKMIP1 and SHB. SUBCELLULAR LOCATION: Endomembrane system; Peripheral membrane protein. Note=Wholly intracellular, possibly membrane associated. TISSUE SPECIFICITY: Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue. DOMAIN: Possesses two phosphotransferase domains. The second one probably contains the catalytic domain (By similarity), while the presence of slight differences suggest a different role for domain 1. DOMAIN: The FERM domain mediates interaction with JAKMIP1. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. SIMILARITY: Contains 1 FERM domain. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 SH2 domain. SEQUENCE CAUTION: Sequence=AAA36527.1; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=AAA36527.1; Type=Frameshift; Positions=858, 862; GENE SYNONYMS: JAK1A JAK1B. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex1118
IL6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs:p-SHP2
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Complex682
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_3918.1
Interleukin-6 receptor subunit alpha short soluble form
Original RDFId (before applying ReactomeCleaner): http://www.reactome.org/biopax/48887#Protein1642
Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=REACT_27647.1
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=59282
Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=59284