BioPAX pathway converted from "Fc epsilon receptor (FCERI) signaling" in the Reactome database. Fc epsilon receptor (FCERI) signaling Fc epsilon receptor (FCERI) signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> IgE binds FCERI IgE binds FCERI This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9812787 1 extracellular region GO 0005576 IgE [extracellular region] IgE Reactome DB_ID: 9812785 1 IgE Heavy Chain [extracellular region] IgE Heavy Chain Converted from EntitySet in Reactome Reactome DB_ID: 9763641 1 Ig Heavy Chain V Region [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ighv3-6 [extracellular region] Ighv1-22 [extracellular region] Ighv5-17 [extracellular region] Ighv1-82 [extracellular region] Ighv1-53 [extracellular region] Ighv8-9 [extracellular region] Ighv14-3 [extracellular region] Ighv1-15 [extracellular region] Ighv1-4 [extracellular region] Ighv14-1 [extracellular region] Ighv8-5 [extracellular region] Ighv5-6 [extracellular region] Ighv14-4 [extracellular region] Ighv1-23 [extracellular region] Ighv1-55 [extracellular region] Ighv3-1 [extracellular region] Ighv1-24 [extracellular region] Ighv1-43 [extracellular region] Ighv1-62-3 [extracellular region] Ighv8-13 [extracellular region] Ighv3-8 [extracellular region] Ighv3-1 [extracellular region] Ighv1-4 [extracellular region] Ighv3-3 [extracellular region] Ighv1-26 [extracellular region] Ighv8-12 [extracellular region] Ighv1-75 [extracellular region] Ighv1-54 [extracellular region] Ighv1-80 [extracellular region] Ighv15-2 [extracellular region] Ighv5-9 [extracellular region] Ighv8-2 [extracellular region] Ighv1-80 [extracellular region] Ighv12-3 [extracellular region] Ighv14-2 [extracellular region] Ighv1-16 [extracellular region] Ighv5-4 [extracellular region] Ighv5-12-4 [extracellular region] Ighv1-61 [extracellular region] Ighv1-58 [extracellular region] Ighv3-4 [extracellular region] Ighv1-56 [extracellular region] Ighv1-5 [extracellular region] Ighv12-3 [extracellular region] Ighv5-16 [extracellular region] Ighv1-9 [extracellular region] Ighv1-7 [extracellular region] Ighv1-77 [extracellular region] Ighv3-4 [extracellular region] Ighv4-1 [extracellular region] P18533 [extracellular region] Ighv1-11 [extracellular region] Ighv3-8 [extracellular region] Gm5629 [extracellular region] Ighv1-47 [extracellular region] Ighv1-12 [extracellular region] Ighv1-63 [extracellular region] Ighv1-69 [extracellular region] Ighv1-72 [extracellular region] Ighv5-12 [extracellular region] Ighv1-59 [extracellular region] Ig heavy chain V-II region ARH-77 [extracellular region] Ighv1-81 [extracellular region] Ighv8-4 [extracellular region] Ighv1-64 [extracellular region] Ighv8-11 [extracellular region] Ighv8-8 [extracellular region] Ighv11-2 [extracellular region] Ighv1-34 [extracellular region] Ighv1-76 [extracellular region] Ighv5-15 [extracellular region] Ighv1-36 [extracellular region] Ighv1-31 [extracellular region] Ighv1-37 [extracellular region] Ighv1-42 [extracellular region] Ighv1-52 [extracellular region] Ighv1-67 [extracellular region] Ighv1-19 [extracellular region] Ighv5-12 [extracellular region] Ighv1-20 [extracellular region] Ighv11-1 [extracellular region] Ighv1-78 [extracellular region] Ighv1-66 [extracellular region] Ighv1-85 [extracellular region] Ighv5-9-1 [extracellular region] Ighv1-50 [extracellular region] Ighv1-74 [extracellular region] Ighv1-49 [extracellular region] Ighv5-2 [extracellular region] Ighv3-6 [extracellular region] Ighv1-62-2 [extracellular region] Ighv3-3 [extracellular region] Ighv1-18 [extracellular region] Ighv1-39 [extracellular region] Ighv8-6 [extracellular region] Reactome http://www.reactome.org Mus musculus NCBI Taxonomy 10090 UniProt P18531 UniProt A0A075B5U7 UniProt A0A075B5R1 UniProt A0A0B4J1J7 UniProt A0A075B5W3 UniProt A0A075B5X1 UniProt A0A075B5R9 UniProt A0A0A6YXA5 UniProt A0A075B5T4 UniProt A0A075B5R4 UniProt A0A0A6YY60 UniProt A0A075B5Q0 UniProt A0A075B5S3 UniProt A0A0A6YVW3 UniProt A0A075B5W6 UniProt A0A075B5S6 UniProt A0A075B5U9 UniProt A0A075B5V7 UniProt P01754 UniProt A0A075B5Y0 UniProt A0A075B5T0 UniProt A0A075B5S4 UniProt A0A075B5V0 UniProt A0A075B5X8 UniProt A0A075B5Y2 UniProt A0A075B5W5 UniProt A0A075B5Y3 UniProt A0A075B5T8 UniProt A0A075B5Q2 UniProt A0A0A6YW58 UniProt A0A075B5T1 UniProt A0A075B5R7 UniProt A0A075B5U1 UniProt A0A075B5P9 UniProt A0A0A6YWG4 UniProt P01749 UniProt A0A075B5W9 UniProt A0A0A6YXF1 UniProt A0A075B5W7 UniProt A0A075B5T5 UniProt A0A075B5R0 UniProt A0A075B5T9 UniProt A0A075B5T7 UniProt A0A0B4J1M0 UniProt A0A075B5R5 UniProt P18533 UniProt A0A0A6YWI9 UniProt P06327 UniProt A0A075B5V8 UniProt A0A075B5U0 UniProt A0A075B5X2 UniProt A0A075B5X7 UniProt P06328 UniProt A0A075B5Q4 UniProt A0A075B5X0 UniProt A0A075B5Y4 UniProt A0A075B693 UniProt A0A075B5X3 UniProt A0A075B5X4 UniProt A0A0A6YXQ0 UniProt A0A075B5R8 UniProt A0A075B5V2 UniProt A0A0B4J1N0 UniProt A0A075B5Q9 UniProt A0A075B5V3 UniProt A0A075B5V1 UniProt A0A075B5V4 UniProt A0A075B5V6 UniProt A0A075B5W2 UniProt A0A075B5X6 UniProt A0A075B5U5 UniProt A0A075B5U6 UniProt A0A075B5R6 UniProt A0A075B674 UniProt A0A075B5X5 UniProt A0A075B5Y6 UniProt A0A075B5Q6 UniProt A0A075B5W1 UniProt A0A075B5Y1 UniProt A0A075B5V9 UniProt A0A075B5P7 UniProt A0A075B680 UniProt A0A075B5U4 UniProt A0A075B5V5 UniProt A0A075B5W4 Reactome DB_ID: 9812783 1 Ghost homologue of IGHE [extracellular region] Ghost homologue of IGHE Reactome Database ID Release 78 9812785 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=9812785 Reactome R-MMU-1591209 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=R-MMU-1591209.1 Reactome DB_ID: 9763277 1 Immunoglobulin Kappa Light Chain [extracellular region] Immunoglobulin Kappa Light Chain Reactome DB_ID: 9763141 1 UniProt:P01837 Igkc Igkc Igkc SIMILARITY Contains 1 Ig-like (immunoglobulin-like) domain. UniProt P01837 Chain Coordinates 1 EQUAL 106 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9763275 1 Ig Kappa Light Chain V Region [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Igkv1-133 [extracellular region] Ighv1-4 [extracellular region] Gm42543 [extracellular region] Igkv20-101-2 [extracellular region] Igkv1-131 [extracellular region] Igkv10-96 [extracellular region] Igkv10-94 [extracellular region] Igkv9-123 [extracellular region] Igkv9-124 [extracellular region] Igkv1-132 [extracellular region] Igkv9-124 [extracellular region] Ighv1-80 [extracellular region] Gm5153 [extracellular region] Igkv1-35 [extracellular region] Igkv10-96 [extracellular region] Igkv1-35 [extracellular region] Igkv8-21 [extracellular region] Igkv10-95 [extracellular region] Igkv20-101-2 [extracellular region] Igkv18-36 [extracellular region] Igkv10-94 [extracellular region] Igkv1-135 [extracellular region] Igkv20-101-2 [extracellular region] Gm5571 [extracellular region] Gm42543 [extracellular region] Igkv10-95 [extracellular region] Igkv13-84 [extracellular region] Gm5571 [extracellular region] Gm42543 [extracellular region] Igkv17-127 [extracellular region] Igkv9-123 [extracellular region] Igkv2-137 [extracellular region] Igkv17-121 [extracellular region] UniProt A0A0B4J1H8 UniProt A0A0G2JET4 UniProt A0A0G2JDU3 UniProt A0A140T8M8 UniProt A0A140T8M1 UniProt A0A075B5L1 UniProt A0A140T8N8 UniProt A0A075B5K2 UniProt A0A0B4J1H9 UniProt P01627 UniProt A0A075B5N0 UniProt A0A140T8P7 UniProt A0A075B5L0 UniProt A0A075B5M9 UniProt A0A0B4J1H7 UniProt P01639 UniProt A0A140T8N3 UniProt A0A075B5J9 UniProt A0A0B4J1H6 UniProt A0A075B5K3 Reactome Database ID Release 78 9763277 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=9763277 Reactome R-MMU-983670 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=R-MMU-983670.1 Reactome Database ID Release 78 9812787 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=9812787 Reactome R-MMU-1591211 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=R-MMU-1591211.1 Reactome DB_ID: 9812781 1 plasma membrane GO 0005886 FCERI [plasma membrane] FCERI Reactome DB_ID: 9812779 1 UniProt:P20490 Ms4a2 UniProt P20490 1 EQUAL 244 EQUAL Reactome DB_ID: 9812775 1 UniProt:P20489 Fcer1a UniProt P20489 26 EQUAL 257 EQUAL Reactome DB_ID: 9759803 1 FCERIG dimer [plasma membrane] FCERIG dimer Reactome DB_ID: 5621125 2 UniProt:P20491 Fcer1g Fcer1g Fcer1g Fce1g FUNCTION Adapter protein containing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. As a component of the high-affinity immunoglobulin E (IgE) receptor, mediates allergic inflammatory signaling in mast cells (PubMed:14764707). As a constitutive component of interleukin-3 receptor complex, selectively mediates interleukin 4/IL4 production by basophils, priming T-cells toward effector T-helper 2 subset (PubMed:19098920). Associates with pattern recognition receptors CLEC4D and CLEC4E to form a functional signaling complex in myeloid cells. Binding of mycobacterial trehalose 6,6'-dimycolate (TDM) to this receptor complex leads to phosphorylation of ITAM, triggering activation of SYK, CARD9 and NF-kappa-B, consequently driving maturation of antigen-presenting cells and shaping antigen-specific priming of T-cells toward effector T-helper 1 and T-helper 17 cell subtypes (PubMed:23602766) (Probable). May function cooperatively with other activating receptors. Functionally linked to integrin beta-2/ITGB2-mediated neutrophil activation (PubMed:17086186). Also involved in integrin alpha-2/ITGA2-mediated platelet activation (PubMed:9171347).SUBUNIT IgE Fc receptor is a tetramer of an alpha chain, a beta chain, and two disulfide linked gamma chains. Associates with FCGR1A; forms a functional signaling complex (By similarity). Associates with CLEC6A (PubMed:17050534). Interacts with CLEC4E (PubMed:23602766, PubMed:18776906). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK, enabling integrin-mediated activation of neutrophils and macrophages (PubMed:17086186). Interacts with CSF2RB and recruits SYK in response to IL3 stimulation; this interaction is direct (PubMed:19098920). Interacts with CD300LH; the interaction may be indirect (PubMed:20817736). Interacts with CD300LD (PubMed:20817736). Interacts with TARM1 (By similarity).TISSUE SPECIFICITY Expressed in mast cells (at protein level) (PubMed:14764707). Expressed in basophils (at protein level) (PubMed:19098920).DISRUPTION PHENOTYPE Knockout mice are resistant to IgE-mediated systemic anaphylaxis.SIMILARITY Belongs to the CD3Z/FCER1G family. UniProt P20491 19 EQUAL 86 EQUAL Reactome Database ID Release 78 9759803 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=9759803 Reactome R-MMU-210223 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=R-MMU-210223.1 Reactome Database ID Release 78 9812781 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=9812781 Reactome R-MMU-2454198 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=R-MMU-2454198.1 Reactome DB_ID: 9812789 1 FCERI:IgE [plasma membrane] FCERI:IgE Reactome DB_ID: 9812787 1 Reactome DB_ID: 9812781 1 Reactome Database ID Release 78 9812789 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=9812789 Reactome R-MMU-2454224 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=R-MMU-2454224.1 Reactome Database ID Release 78 9859721 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=9859721 Reactome R-MMU-9725206 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=R-MMU-9725206.1 Immunoglobulin-E (IgE)-mediated allergic responses require the binding of the IgE antibody to its high-affinity receptor, Fc epsilonRI (FCERI). Binding of one receptor blocks the binding of a second receptor. After this antigens can bind and crosslink IgE molecules held at the cell surface by FCERI (Garman et al. 2000). 10917520 Pubmed 2000 Structure of the Fc fragment of human IgE bound to its high-affinity receptor Fc epsilonRI alpha Garman, S C Wurzburg, B A Tarchevskaya, S S Kinet, J P Jardetzky, T S Nature 406:259-66 inferred by electronic annotation IEA GO IEA IgE binds omalizumab IgE binds omalizumab This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9724689 1 omalizumab [Guide to Pharmacology:6890] omalizumab Xolair&reg; RG-3648 R03DX05 rhumab-E25 olizumab IGE25 Guide to Pharmacology 6890 Reactome DB_ID: 9812787 1 Reactome DB_ID: 9859717 1 IgE:omalizumab [extracellular region] IgE:omalizumab Reactome DB_ID: 9724689 1 Reactome DB_ID: 9812787 1 Reactome Database ID Release 78 9859717 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=9859717 Reactome R-MMU-9724684 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=R-MMU-9724684.1 Reactome Database ID Release 78 9859719 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=9859719 Reactome R-MMU-9724685 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=R-MMU-9724685.1 When bound to the high-affinity IgE receptor (FCERI), IgE acts as an environmental sensor that detects allergens and induces allergic responses from the cell's interior. Omalizumab is a monoclonal antibody that binds free IgE preventing it from binding to FCERI. Moreover, reduction of free IgE concentrations reduce FCERI expression level. Omalizumab is approved for the treatment of patients with severe allergic asthma. Use of omalizumab is associated with several side effects, including injection site reactions, viral and upper respiratory tract infections, headache, sinusitis, and pharyngitis. The main severe adverse effect is anaphylactic shock, with a rate of occurrence of 1 to 2 patients per 1,000 (Davydov 2005, Arm et al. 2014). 15686303 Pubmed 2005 Omalizumab (Xolair) for treatment of asthma Davydov, Liya Am Fam Physician 71:341-2 25200415 Pubmed 2014 Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects Arm, J P Bottoli, I Skerjanec, A Floch, D Groenewegen, A Maahs, S Owen, C E Jones, I Lowe, P J Clin. Exp. Allergy 44:1371-85 inferred by electronic annotation IEA GO IEA Allergen dependent IgE bound FCERI aggregation Allergen dependent IgE bound FCERI aggregation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9812789 5 Reactome DB_ID: 2454186 1 Allergen [extracellular region] Allergen Reactome DB_ID: 9812793 1 FCERI:IgE:Allergen aggregate [plasma membrane] FCERI:IgE:Allergen aggregate Reactome DB_ID: 2454186 1 Reactome DB_ID: 9812791 1 FCERI:IgE aggregate [plasma membrane] FCERI:IgE aggregate Reactome Database ID Release 78 9812793 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=9812793 Reactome R-MMU-2454196 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=R-MMU-2454196.1 Reactome Database ID Release 78 9812795 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=9812795 Reactome R-MMU-2454192 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=R-MMU-2454192.1 FCERI is primarily expressed on mast cells and basophils as a tetrameric complex comprising an IgE-binding alpha subunit, a signal amplifying membrane-tetraspanning beta subunit, and a disulfide-linked gamma chain dimer that provides the receptor its signaling competence (Blank & Rivera 2004). In the absence of an antigen or allergen, FCERI receptor binds to monomeric IgE antibodies, and thus the receptor adopts the antigenic specificity of the prevalent IgE repertoire (Garman et al. 2000). Mast cell activation is initiated when multivalent antigen crosslinks the IgE bound to the high-affinity FCERI, thereby aggregating FCERI (Siraganian 2003). Antigen driven aggregation of FCERI then elicits intracellular signals that result in mast cell exocytosis. 15099567 Pubmed 2004 The ins and outs of IgE-dependent mast-cell exocytosis Blank, Ulrich Rivera, Juan Trends Immunol. 25:266-73 14630197 Pubmed 2003 Mast cell signal transduction from the high-affinity IgE receptor Siraganian, Reuben P Curr. Opin. Immunol. 15:639-46 17498065 Pubmed 2007 Insights into immunoglobulin E receptor signaling from structurally defined ligands Holowka, David Sil, Dwaipayan Torigoe, Chikako Baird, Barbara Immunol. Rev. 217:269-79 inferred by electronic annotation IEA GO IEA 2.7.10 Autophosphorylation of LYN kinase Autophosphorylation of LYN kinase This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 cytosol GO 0005829 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 9814028 1 UniProt:P25911 Lyn Lyn Lyn FUNCTION Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-96'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (PubMed:28098138). Phosphorylates CLNK (PubMed:12681493).ACTIVITY REGULATION Subject to autoinhibition, mediated by intramolecular interactions between the SH2 domain and the C-terminal phosphotyrosine. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylated by CSK at Tyr-508; phosphorylation at Tyr-508 inhibits kinase activity. Kinase activity is modulated by dephosphorylation by PTPRC/CD45. Inhibited by dasatinib, PP2, and SU6656.SUBUNIT Interacts with TEC. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with LIME1 and with CD79A upon activation of the B-cell antigen receptor. Interacts with the B-cell receptor complex. Interacts with phosphorylated THEMIS2. Interacts with EPOR. Interacts with MS4A2/FCER1B. Interaction (via the SH2 and SH3 domains) with MUC1 is stimulated by IL7 and the subsequent phosphorylation increases the binding between MUC1 and CTNNB1/beta-catenin. Interacts with ADAM15. Interacts with NDFIP2 and more weakly with NDFIP1. Interacts with FASLG. Interacts with KIT. Interacts with HCLS1. Interacts with FCGR2B. Interacts with FCGR1A; the interaction may be indirect. Interacts with CD19, CD22, CD79A and CD79B. Interacts (via SH3 domain) with CBLC, PPP1R15A and PDE4A. Interacts with TGFB1I1. Interacts (via SH3 domain) with PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase; this interaction enhances phosphatidylinositol 3-kinase activity. Interacts with CSF2RB, the common subunit of the IL3, IL5 and CSF2 receptors. Interacts with PAG1; identified in a complex with PAG1 and STAT3. Interacts with ABL1. Interacts with PTPN6/SHP-1. Interacts (via SH3 domain) with SCIMP (via proline-rich region) (PubMed:28098138). This interaction facilitates the phosphorylation of SCIMP on 'Tyr-96', which enhances binding of SCIMP to TLR4, and consequently the phosphorylation of TLR4 in response to stimulation by lipopolysaccharide in macrophages (PubMed:28098138). Interacts with LPXN (via LD motif 3) and the interaction is induced upon B-cell antigen receptor (BCR) activation. Interacts (via SH3-domain) with ANKRD54 (via ankyrin repeat region) in an activation-independent status of LYN. Forms a multiprotein complex with ANKRD54 and HCLS1. Interacts (via SH2 and SH3 domains) with UNC119; leading to LYN activation (By similarity). Interacts with CD36. Interacts with LYN (PubMed:22496641). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (PubMed:12681493).TISSUE SPECIFICITY Detected in bone marrow-derived monocytes and macrophages (at protein level) (PubMed:28098138, PubMed:2017160). Expressed predominantly in B-lymphoid and myeloid cells (PubMed:2017160).DOMAIN The protein kinase domain plays an important role in its localization in the cell membrane.PTM Ubiquitinated by CBL, leading to its degradation.PTM Phosphorylated on tyrosine residues in response to KIT signaling (By similarity). Autophosphorylated. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylation at Tyr-508 inhibits kinase activity. Phosphorylated at Tyr-508 by CSK. Dephosphorylated by PTPRC/CD45. Becomes rapidly phosphorylated upon activation of the B-cell receptor and the immunoglobulin receptor FCGR1A.DISRUPTION PHENOTYPE No visible phenotype at birth. B-cell development in the bone marrow proceeds normally, but mice have reduced numbers of peripheral B-cells, with a greater proportion of immature cells and an increased turnover rate. Dendritic cells also have a more immature phenotype. Mice develop severe asthma upon exposure to airborne antigen. Mice display elevated levels of serum IgM. Aging mice display strongly increased levels of myeloid cells, severe extramedullary hematoipoiesis and tend to develop monocyte/macrophage tumors. After about 16 weeks, mice begin to develop splenomegaly and glomerulonephritis, and display autoimmune antibodies. Their B-cells are hypersensitive to stimulation of the B-cell receptor, and display enhanced activation of the MAP kinase signaling pathway. Mice do not display an allergic response upon IgE receptor engagement.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P25911 2 EQUAL 512 EQUAL Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 9812798 1 O4'-phospho-L-tyrosine at 396 (in Homo sapiens) 396 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 2 EQUAL 512 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9814028 2 EQUAL 512 EQUAL GO 0004713 GO molecular function Reactome Database ID Release 78 9814029 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=9814029 Reactome Database ID Release 78 9814031 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=9814031 Reactome R-MMU-2730862 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=R-MMU-2730862.1 LYN localized in lipid rafts undergoes an intermolecular autophosphorylation at tyrosine 396. This residue is present in the activation loop, and its phosphorylation promotes LYN kinase activity. 9477973 Pubmed 1998 Spontaneous autophosphorylation of Lyn tyrosine kinase at both its activation segment and C-terminal tail confers altered substrate specificity Donella-Deana, A Cesaro, L Ruzzene, M Brunati, A M Marin, O Pinna, L A Biochemistry 37:1438-46 inferred by electronic annotation IEA GO IEA 2.7.10 Phosphorylation of beta and gamma subunits by LYN Phosphorylation of beta and gamma subunits by LYN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 5 Reactome DB_ID: 9812798 1 O4'-phospho-L-tyrosine at 396 (in Homo sapiens) 396 EQUAL 2 EQUAL 512 EQUAL Reactome DB_ID: 9812793 1 Reactome DB_ID: 29370 5 Reactome DB_ID: 9812815 1 Allergen:p-LYN:p-FCERI:IgE aggregate [plasma membrane] Allergen:p-LYN:p-FCERI:IgE aggregate Reactome DB_ID: 2454186 1 Reactome DB_ID: 9812813 1 p-LYN:p-FCERI:IgE aggregate [plasma membrane] p-LYN:p-FCERI:IgE aggregate Reactome DB_ID: 9812787 1 Reactome DB_ID: 9812798 1 O4'-phospho-L-tyrosine at 396 (in Homo sapiens) 396 EQUAL 2 EQUAL 512 EQUAL Reactome DB_ID: 9812811 1 p-FCERI aggregate [plasma membrane] p-FCERI aggregate Reactome Database ID Release 78 9812813 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=9812813 Reactome R-MMU-2454169 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=R-MMU-2454169.1 Reactome Database ID Release 78 9812815 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=9812815 Reactome R-MMU-2454232 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=R-MMU-2454232.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9812798 O4'-phospho-L-tyrosine at 396 (in Homo sapiens) 396 EQUAL 2 EQUAL 512 EQUAL Reactome Database ID Release 78 9812816 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=9812816 Reactome Database ID Release 78 9812818 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=9812818 Reactome R-MMU-2454208 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=R-MMU-2454208.1 Upon FCGRI-IgE aggregation, LYN kinase phosphorylates the tyrosine residues within the ITAM (immunoreceptor tyrosine-based activation motifs) of both the beta and gamma subunits. The detailed mechanism of the initial engagement of LYN kinase and FCERI is incompletely understood, but two different models have been proposed. One model postulates that a small fraction of LYN is constitutively bound to beta subunit of FCERI prior to activation. Aggregation of FCERI facilitates the transphosphorylation of one FCERI by LYN bound to a juxtaposed receptor (Vonakis et al. 1997, Draber & Draberova 2002). Alternative model postulates that LYN is observed in lipid rafts enriched in glycosphingolipids, cholesterol, and glycosylphosphatidylinositol-anchored proteins and upon aggregation, FCERI rapidly translocates into lipid rafts, where it is phosphorylated by LYN kinase. Either the association of LYN or FCERI or both with lipid rafts is important for initiating this phosphorylation process (Young et al. 2003, Kovarova et al. 2002, Draber & Draberova 2002).<br>Beta subunit ITAM differs from canonical ITAMs in two ways; the spacing between the two canonical tyrosines harbours a third tyrosine, and it is one amino acid shorter than in canonical ITAMs, thus making it unfit to bind and recruit Syk. Among the three tyrosine residues (Y219, Y225 and Y229), Y219 may play a predominant role in beta chain function and LYN recruitment. Mutation of this tyrosine would decrease substantially LYN association and subsequent phosphorylation of Y225 and Y229. This would result in decreased gamma phosphorylation and decreased SYK recruitment and activation (On et al. 2004). 7526393 Pubmed 1994 Transphosphorylation as the mechanism by which the high-affinity receptor for IgE is phosphorylated upon aggregation Pribluda, V S Pribluda, C Metzger, H Proc. Natl. Acad. Sci. U.S.A. 91:11246-50 12670955 Pubmed 2003 A lipid raft environment enhances Lyn kinase activity by protecting the active site tyrosine from dephosphorylation Young, Ryan M Holowka, David Baird, Barbara J. Biol. Chem. 278:20746-52 12217391 Pubmed 2002 Lipid rafts in mast cell signaling Dráber, Petr Dráberová, Lubica Mol. Immunol. 38:1247-52 9295361 Pubmed 1997 The unique domain as the site on Lyn kinase for its constitutive association with the high affinity receptor for IgE Vonakis, B M Chen, H Haleem-Smith, H Metzger, H J. Biol. Chem. 272:24072-80 11713268 Pubmed 2001 Structure-function analysis of Lyn kinase association with lipid rafts and initiation of early signaling events after Fcepsilon receptor I aggregation Kovárová, M Tolar, P Arudchandran, R Dráberová, L Rivera, J Dráber, P Mol. Cell. Biol. 21:8318-28 inferred by electronic annotation IEA GO IEA Recruitment of SYK to p-FCERI gamma subunit Recruitment of SYK to p-FCERI gamma subunit This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9812815 1 Reactome DB_ID: 9759903 1 UniProt:P48025 Syk Syk ptk72 Syk Sykb FUNCTION Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Required for the stimulation of neutrophil phagocytosis by IL15 (By similarity). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils (PubMed:19098920). Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (PubMed:26195794).ACTIVITY REGULATION Autoinhibited. Intramolecular binding of the interdomains A and B (also called linker region) to parts of the catalytic domain keep the catalytic center in an inactive conformation. The phosphorylation of the interdomains or the binding of the SH2 domains with dually phosphorylated ITAM domains on transmembrane proteins disrupt those intramolecular interactions allowing the kinase domain to adopt an active conformation. The phosphorylation of SYK and of the ITAM domains which is responsible for SYK activation is essentially mediated by SRC subfamily kinases, like LYN, upon transmembrane receptors engagement. May also be negatively regulated by PTPN6 through dephosphorylation (By similarity). Downstream signaling adapters and intermediates like BLNK or RHOH may mediate positive and/or negative feedback regulation. Negatively regulated by CBL and CBLB through ubiquitination and probable degradation. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN (By similarity).SUBUNIT Interacts with LYN; phosphorylates SYK. Interacts with RHOH (phosphorylated); regulates mast cells activation. Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling. Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation (By similarity). Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling. Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation. Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation. Interaction with FCER1G in basophils triggers IL3-induced IL4 production (PubMed:19098920). Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling. Interacts with ITGB3; upon activation by ITGB3 promotes platelet adhesion (By similarity). Interacts (via SH2 domains) with TYROBP (via ITAM domain); involved in neutrophils and macrophages integrin-mediated activation. Interacts with MSN and SELPLG; mediates the selectin-dependent activation of SYK by SELPLG (By similarity). Interacts with BLNK (via SH2 domain). Interacts (via the second SH2 domain) with USP25 (via C-terminus); phosphorylates USP25 and regulates USP25 intracellular levels (By similarity). Interacts (via SH2 domains) with CLEC1B (dimer) (By similarity). Interacts with CLEC7A; participates in leukocyte activation in presence of fungal pathogens. Interacts (phosphorylated) with SLA; may regulate SYK through CBL recruitment (By similarity). Interacts with YWHAG; attenuates BCR-induced membrane translocation and activation of SYK (By similarity). Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity (By similarity). Interacts with TNS2; leading to the phosphorylation of SYK (By similarity). Interacts with FLNA (via filamin repeat 5); docks SYK to the plasma membrane (By similarity). Interacts with CEACAM1; lipopolysaccharide activated neutrophils induce phosphorylation of SYK resulting in the formation of a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, leading to a reduction of the inflammasome activity (PubMed:22496641). Interacts (via SH2 domains) with CEACAM20 (phosphorylated form); the interaction further enhances CEACAM20 phosphorylation (PubMed:26195794). Interacts with IL15RA (By similarity).DOMAIN The SH2 domains mediate the interaction of SYK with the phosphorylated ITAM domains of transmembrane proteins. Some proteins like CLEC1B have a partial ITAM domain (also called hemITAM) containing a single YxxL motif. The interaction with SYK requires CLEC1B homodimerization (By similarity).PTM Autophosphorylated. Phosphorylated on tyrosine residues by LYN following receptors engagement. Phosphorylation on Tyr-317 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-342 creates a binding site for VAV1 (By similarity). Phosphorylation on Tyr-342 and Tyr-346 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of calcium ion mobilization via a phosphoinositide 3-kinase-independent pathway (By similarity). Phosphorylated on tyrosine residues in response to IL15 (By similarity). Phosphorylation on Ser-291 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG (By similarity). Phosphorylation at Tyr-624 creates a binding site for BLNK (By similarity). Dephosphorylated by PTPN6 (By similarity).PTM Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation.DISRUPTION PHENOTYPE Embryos display severe systemic hemorrhage and mice are not viable dying perinatally. While T-cells development is not affected, the development of B-cells is impaired most probably at the pro-B to pre-B transition and mice lack mature B-cells.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily. UniProt P48025 1 EQUAL 635 EQUAL Reactome DB_ID: 9812820 1 Clustered p:LYN:p-FCERI:IgE:allergen:SYK [plasma membrane] Clustered p:LYN:p-FCERI:IgE:allergen:SYK Reactome DB_ID: 9812815 1 Reactome DB_ID: 9759903 1 1 EQUAL 635 EQUAL Reactome Database ID Release 78 9812820 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=9812820 Reactome R-MMU-2454243 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=R-MMU-2454243.1 Reactome Database ID Release 78 9812822 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=9812822 Reactome R-MMU-2454240 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=R-MMU-2454240.1 Tyrosine phosphorylated ITAM in FCERI gamma subunit serves as docking site for SYK (spleen tyrosine kinases), whereas the beta-subunit ITAM has an extra tyrosine and is shorter than canonical ITAM which makes it unfit to bind SYK. Association of SYK to FCERI gamma-subunit disrupts the COOH-terminal-SH2 interdomain interaction of SYK causing a conformational change opening the molecule leading to its activation (Siraganian et al. 2010, de Castro et al. 2010). 8910399 Pubmed 1996 Downstream signaling molecules bind to different phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) peptides of the high affinity IgE receptor Kimura, T Kihara, H Bhattacharyya, S Sakamoto, H Appella, E Siraganian, R P J. Biol. Chem. 271:27962-8 8071371 Pubmed 1994 Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor Kihara, H Siraganian, R P J. Biol. Chem. 269:22427-32 20696166 Pubmed 2010 Mast cell signaling: the role of protein tyrosine kinase Syk, its activation and screening methods for new pathway participants Siraganian, Reuben P de Castro, Rodrigo O Barbu, Emilia A Zhang, Juan FEBS Lett. 584:4933-40 7528327 Pubmed 1995 Interaction of p72syk with the gamma and beta subunits of the high-affinity receptor for immunoglobulin E, Fc epsilon RI Shiue, L Green, J Green, O M Karas, J L Morgenstern, J P Ram, M K Taylor, M K Zoller, M J Zydowsky, L D Bolen, J B Mol. Cell. Biol. 15:272-81 20554527 Pubmed 2010 Tyrosines in the carboxyl terminus regulate Syk kinase activity and function de Castro, Rodrigo O Zhang, Juan Jamur, Maria C Oliver, Constance Siraganian, Reuben P J. Biol. Chem. 285:26674-84 inferred by electronic annotation IEA GO IEA 2.7.10 Phosphorylation of LAT by p-SYK Phosphorylation of LAT by p-SYK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 5 Reactome DB_ID: 9771256 1 UniProt:O54957 Lat UniProt O54957 1 EQUAL 262 EQUAL Reactome DB_ID: 29370 5 Reactome DB_ID: 9812145 1 O4'-phospho-L-tyrosine at 127 (in Homo sapiens) 127 EQUAL O4'-phospho-L-tyrosine at 132 (in Homo sapiens) 132 EQUAL O4'-phospho-L-tyrosine at 171 (in Homo sapiens) 171 EQUAL O4'-phospho-L-tyrosine at 191 (in Homo sapiens) 191 EQUAL O4'-phospho-L-tyrosine at 226 (in Homo sapiens) 226 EQUAL 1 EQUAL 262 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813910 Clustered p:LYN:p-FCERI:IgE:allergen:p-6Y-SYK [plasma membrane] Clustered p:LYN:p-FCERI:IgE:allergen:p-6Y-SYK Reactome DB_ID: 9794521 1 O4'-phospho-L-tyrosine at 348 348 EQUAL O4'-phospho-L-tyrosine at 352 352 EQUAL O4'-phospho-L-tyrosine at 525 525 EQUAL O4'-phospho-L-tyrosine at 526 526 EQUAL O4'-phospho-L-tyrosine at 131 (in Homo sapiens) 131 EQUAL O4'-phospho-L-tyrosine at 323 (in Homo sapiens) 323 EQUAL 1 EQUAL 635 EQUAL Reactome DB_ID: 9812815 1 Reactome Database ID Release 78 9813910 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=9813910 Reactome R-MMU-2454231 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=R-MMU-2454231.1 Reactome Database ID Release 78 9813911 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=9813911 Reactome Database ID Release 78 9813962 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=9813962 Reactome R-MMU-2730843 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=R-MMU-2730843.1 LAT is palmitoylated and membrane-associated adaptor protein. It rapidly becomes tyrosine-phosphorylated upon receptor engagement. LAT has nine conserved tyrosine residues of which five have been shown to undergo phosphorylation (Y127, Y132, Y171, Y191 and Y226). Src family kinases, SYK and ZAP-70 efficiently phosphorylate LAT on these tyrosine residues (Jiang & Cheng 2007, Paz et al. 2001). Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domain proteins PLC-gamma1, GRB2 and GADS, which indirectly bind SOS, VAV, SLP-76 and ITK (Wange 2000). 11368773 Pubmed 2001 Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells Paz, P E Wang, S Clarke, H Lu, X Stokoe, D Abo, Arie Biochem. J. 356:461-71 11752630 Pubmed 2000 LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways Wange, RL Sci STKE 2000:RE1 10072481 Pubmed 1999 Cutting edge: a role for the adaptor protein LAT in human NK cell-mediated cytotoxicity Jevremovic, D Billadeau, D D Schoon, R A Dick, C J Irvin, B J Zhang, W Samelson, L E Abraham, Robert T Leibson, P J J. Immunol. 162:2453-6 16938345 Pubmed 2007 Evidence of LAT as a dual substrate for Lck and Syk in T lymphocytes Jiang, Y Cheng, H Leuk Res 31:541-5 inferred by electronic annotation IEA GO IEA FCERI mediated MAPK activation FCERI mediated MAPK activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.10 Phosphorylation of SHC by SYK kinase Phosphorylation of SHC by SYK kinase This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 3 Reactome DB_ID: 9814104 1 UniProt:P98083 Shc1 Shc1 Shc1 ShcA Shc FUNCTION Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis (By similarity). Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p47Shc and isoform p52Shc, once phosphorylated, couple activated receptor kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p47Shc and isoform p52 may thus function as initiators of the Ras signaling cascade in various non-neuronal systems. Isoform p66Shc does not mediate Ras activation, but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and life span. Isoform p66Shc acts as a downstream target of the tumor suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. The expression of isoform p66Shc has been correlated with life span.SUBUNIT Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (By similarity). Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. Once activated, binds to GRB2. Interacts with tyrosine-phosphorylated DDR2 and CD3T. Interacts with the N-terminal region of APS. Interacts with GRB7 and KIT (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with phosphorylated LRP1 and IRS4. Interacts with FLT4 (tyrosine-phosphorylated) (By similarity). Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4 (By similarity). Interacts with TEK/TIE2 (tyrosine-phosphorylated) (By similarity). Interacts with ALK, GAB2, TRIM31, INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with CEACAM1; this interaction is CEACAM1-phosphorylation-dependent and mediates interaction with EGFR or INSR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity) (PubMed:15467833). Interacts (via PID domain) with PEAK1 (when phosphorylated at 'Tyr-1177') (By similarity). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (By similarity).TISSUE SPECIFICITY Widely expressed. Expressed in neural stem cells but absent in mature neurons.DOMAIN In response to a variety of growth factors, isoform p47Shc and isoform p52 bind to phosphorylated receptors through their phosphotyrosine binding (PID) and/or SH2 domains. The PID and SH2 domains bind to specific phosphorylated tyrosine residues in the Asn-Pro-Xaa-Tyr(P) motif. Isoform p47Shc and isoform p52Shc are in turn phosphorylated on three tyrosine residues within the extended proline-rich domain. These phosphotyrosines act as docking site for GRB2 and thereby are involved in Ras activation.PTM Phosphorylated in response to FLT4 signaling (By similarity). Tyrosine phosphorylated by ligand-activated PDGFRB (By similarity). May be tyrosine phosphorylated by activated PTK2/FAK1 (By similarity). Tyrosine phosphorylated by TEK/TIE2 (By similarity). Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity). Dephosphorylation by PTPN2 may regulate interaction with GRB2 (By similarity). Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to KIT signaling. Isoform p47Shc and isoform p52Shc are phosphorylated on tyrosine residues of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36 by PRKCB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light. FLT3 signaling promotes tyrosine phosphorylation of isoform p47Shc and isoform p52Shc. Also tyrosine phosphorylated by ligand-activated ALK. UniProt P98083 111 EQUAL 583 EQUAL Reactome DB_ID: 29370 3 Reactome DB_ID: 9812307 1 O4'-phospho-L-tyrosine at 239 (in Homo sapiens) 239 EQUAL O4'-phospho-L-tyrosine at 240 (in Homo sapiens) 240 EQUAL O4'-phospho-L-tyrosine at 317 (in Homo sapiens) 317 EQUAL 111 EQUAL 583 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813910 Reactome Database ID Release 78 9814106 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=9814106 Reactome R-MMU-2730886 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=R-MMU-2730886.1 SHC is an adapter protein that has been implicated in Ras activation. Mast cells express two isoforms of 46 and 52 kDa. Both isoforms of SHC have two domains, an N-terminal phosphotyrosine-binding (PTB) domain and a C-terminal SH2 domain that allows Shc to bind to proteins containing phosphorylated tyrosine residues. Following receptor stimulation, SHC is phosphorylated by Src kinases Syk on Y239, Y240 and Y317 (p56 isoform). Both phosphotyrosines Y239 and Y317 creates the binding site for the SH2 domain of GRB2. 8663278 Pubmed 1996 Syk-dependent phosphorylation of Shc. A potential link between FcepsilonRI and the Ras/mitogen-activated protein kinase signaling pathway through SOS and Grb2 Jabril-Cuenod, B Zhang, C Scharenberg, A M Paolini, R Numerof, R Beaven, M A Kinet, J P J. Biol. Chem. 271:16268-72 9199344 Pubmed 1997 Shc contains two Grb2 binding sites needed for efficient formation of complexes with SOS in B lymphocytes Harmer, SL DeFranco, AL Mol Cell Biol 17:4087-95 10523831 Pubmed 1999 Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of the Ras/MAP kinase pathway and c-fos induction Lennartsson, J Blume-Jensen, P Hermanson, M Pontén, E Carlberg, M Rönnstrand, Lars Oncogene 18:5546-53 inferred by electronic annotation IEA GO IEA Interaction of GRB2:SOS complex with p-SHC1 Interaction of GRB2:SOS complex with p-SHC1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9812307 1 O4'-phospho-L-tyrosine at 239 (in Homo sapiens) 239 EQUAL O4'-phospho-L-tyrosine at 240 (in Homo sapiens) 240 EQUAL O4'-phospho-L-tyrosine at 317 (in Homo sapiens) 317 EQUAL 111 EQUAL 583 EQUAL Reactome DB_ID: 9756228 1 GRB2-1:SOS1 [cytosol] GRB2-1:SOS1 Reactome DB_ID: 9756226 1 UniProt:Q62245 Sos1 Sos1 Sos1 FUNCTION Promotes the exchange of Ras-bound GDP by GTP. Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (By similarity). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (PubMed:10499589, PubMed:11524436).SUBUNIT Interacts (via C-terminus) with GRB2 (via SH3 domain). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains). Interacts with phosphorylated LAT2. Interacts with NCK1 and NCK2 (By similarity). Part of a complex consisting of ABI1, EPS8 and SOS1 (PubMed:10499589, PubMed:11524436). Interacts (Ser-1120 and Ser-1147 phosphorylated form) with YWHAB and YWHAE (By similarity).TISSUE SPECIFICITY Expressed in most embryonic and adult tissues.PTM Phosphorylation at Ser-1120 and Ser-1147 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation. UniProt Q62245 1 EQUAL 1333 EQUAL Reactome DB_ID: 9756223 1 UniProt:Q60631 Grb2 Grb2 Grb2 FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (By similarity). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (PubMed:8943348). Interacts with IRS4 (when Tyr-phosphorylated) (PubMed:11113178). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (By similarity). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (By similarity). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (By similarity). Interacts with phosphorylated MET (By similarity). Interacts with phosphorylated TOM1L1 (PubMed:11711534). Interacts with the phosphorylated C-terminus of SH2B2 (By similarity). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:16249387, PubMed:14610044, PubMed:15477350, PubMed:15477348, PubMed:22561606). Interacts with NISCH, PTPNS1 and REPS2 (By similarity). Interacts with syntrophin SNTA1 (PubMed:11551227). Interacts (via SH3 domains) with REPS1 (PubMed:9395447). Interacts (via SH3 domains) with PIK3C2B (By similarity). Interacts with CBL and CBLB (By similarity). Interacts with AJUBA and CLNK (PubMed:10330178, PubMed:11463797). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (PubMed:10521483). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (By similarity). Interacts with PTPN11 (PubMed:8943348). Interacts with PRNP (PubMed:11571277). Interacts with RALGPS1 (By similarity). Interacts also with HCST (PubMed:16582911). Interacts with KDR (PubMed:16966330). Interacts with FLT1 (tyrosine-phosphorylated) (PubMed:9722576). Interacts with GAPT and PTPRE (By similarity). Interacts (via SH2 domain) with KIF26A (By similarity). Interacts (via SH3 2) with GAB2 (PubMed:10068651). Interacts with ADAM15 (By similarity). Interacts with THEMIS2 (PubMed:20644716). Interacts (via SH2 domain) with AXL (phosphorylated) (By similarity). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:10377264). Interacts with PTPRJ and BCR (By similarity). Interacts with PTPN23 (By similarity). Interacts with FLT4 (tyrosine phosphorylated) (By similarity). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Part of a complex including TNK2, GRB2 and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (By similarity). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:9312046). Interacts with ERBB4 (By similarity). Interacts with NTRK1 (phosphorylated upon ligand-binding) (By similarity). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:7997267). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (By similarity). Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-58' (PubMed:21930792, PubMed:28098138, PubMed:28290451). Interacts (via SH3 domains) with GAREM1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (By similarity). Interacts with DAB2 (PubMed:9569023). Interacts with TESPA1 (By similarity). Interacts with THEMIS (PubMed:19597498, PubMed:19597497, PubMed:19805304, PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (PubMed:22561606). Interacts with CD28 (By similarity). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (PubMed:21543326). Interacts with ASAP3 (phosphorylated form) (By similarity). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (PubMed:20398064). Interacts with PTPRO (phosphorylated form) (PubMed:20398064). Interacts with PTPRB (phosphorylated form) (PubMed:20398064). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (By similarity). Interacts with DENND2B (By similarity). Interacts with SPRY2 (By similarity). Interacts with LRRC8A (PubMed:32930093).TISSUE SPECIFICITY Expressed in macrophages.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family. UniProt Q60631 1 EQUAL 217 EQUAL Reactome Database ID Release 78 9756228 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=9756228 Reactome R-MMU-109797 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=R-MMU-109797.1 Reactome DB_ID: 9812309 1 p-SHC1:GRB2:SOS [cytosol] p-SHC1:GRB2:SOS Reactome DB_ID: 9812307 1 O4'-phospho-L-tyrosine at 239 (in Homo sapiens) 239 EQUAL O4'-phospho-L-tyrosine at 240 (in Homo sapiens) 240 EQUAL O4'-phospho-L-tyrosine at 317 (in Homo sapiens) 317 EQUAL 111 EQUAL 583 EQUAL Reactome DB_ID: 9756228 1 Reactome Database ID Release 78 9812309 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=9812309 Reactome R-MMU-2685672 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=R-MMU-2685672.1 Reactome Database ID Release 78 9813964 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=9813964 Reactome R-MMU-2730844 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=R-MMU-2730844.1 GRB2 is an adapter protein that contains a central SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). GRB2-SOS complex binds to phosphotyrosine Y239 and Y317 of SHC1. SHC1 associates with the tyrosine-phosphorylated ITAMs of the FCERI beta-chain and can recruit SOS to membrane. SHC1 and SOS have also been described to associate with LAT via GRB2. Shc binding to Phospho-ITAMs (in vitro binding to phospho peptides) has never been linked to any biological function (activation) and is probably not relevant in a physiological setting. 19909365 Pubmed 2009 Adapters in the organization of mast cell signaling Alvarez-Errico, Damiana Lessmann, Eva Rivera, Juan Immunol. Rev. 232:195-217 8493579 Pubmed 1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2 Chardin, P Camonis, JH Gale, NW Van Aelst, L Schlessinger, J Wigler, Michael H Bar-Sagi, Dafna Science 260:1338-43 17365510 Pubmed 2007 Analysis of proteins binding to the ITAM motif of the beta-subunit of the high-affinity receptor for IgE (FcepsilonRI) Soto-Cruz, Isabel Oliver, Janet M Ortega, Enrique J. Recept. Signal Transduct. Res. 27:67-81 inferred by electronic annotation IEA GO IEA Recruitment of GRB2:SOS to p-5Y-LAT Recruitment of GRB2:SOS to p-5Y-LAT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9812309 1 Reactome DB_ID: 9812145 1 O4'-phospho-L-tyrosine at 127 (in Homo sapiens) 127 EQUAL O4'-phospho-L-tyrosine at 132 (in Homo sapiens) 132 EQUAL O4'-phospho-L-tyrosine at 171 (in Homo sapiens) 171 EQUAL O4'-phospho-L-tyrosine at 191 (in Homo sapiens) 191 EQUAL O4'-phospho-L-tyrosine at 226 (in Homo sapiens) 226 EQUAL 1 EQUAL 262 EQUAL Reactome DB_ID: 9812311 1 p-5Y-LAT:p-SHC1:GRB2:SOS1 [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1 Reactome DB_ID: 9812309 1 Reactome DB_ID: 9812145 1 O4'-phospho-L-tyrosine at 127 (in Homo sapiens) 127 EQUAL O4'-phospho-L-tyrosine at 132 (in Homo sapiens) 132 EQUAL O4'-phospho-L-tyrosine at 171 (in Homo sapiens) 171 EQUAL O4'-phospho-L-tyrosine at 191 (in Homo sapiens) 191 EQUAL O4'-phospho-L-tyrosine at 226 (in Homo sapiens) 226 EQUAL 1 EQUAL 262 EQUAL Reactome Database ID Release 78 9812311 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=9812311 Reactome R-MMU-2424468 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=R-MMU-2424468.1 Reactome Database ID Release 78 9812325 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=9812325 Reactome R-MMU-2396599 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=R-MMU-2396599.1 GRB2 is an adapter protein that contains a central SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). Following phosphorylation of LAT, the GRB2:SOS complex binds to the phosphorylated tyrosines and is thereby translocated to the inner face of the plasma membrane where inactive RAS:GDP resides. The three distal tyrosines, Y171, Y191 and Y226 of LAT are responsible for GRB2 association (Balagopalan et al. 2010, Zhang et al. 2000). 20610546 Pubmed 2010 The LAT story: a tale of cooperativity, coordination, and choreography Balagopalan, Lakshmi Coussens, Nathan P Sherman, Eilon Samelson, Lawrence E Sommers, Connie L Cold Spring Harb Perspect Biol 2:a005512 10811803 Pubmed 2000 Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. Zhang, W Trible, RP Zhu, M Liu, SK McGlade, CJ Samelson, LE J Biol Chem 275:23355-61 inferred by electronic annotation IEA GO IEA SOS mediated nucleotide exchange of RAS (SHC) SOS mediated nucleotide exchange of RAS (SHC) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9766393 1 p21 RAS:GDP [plasma membrane] p21 RAS:GDP Reactome DB_ID: 29420 1 GDP(3-) [ChEBI:58189] GDP(3-) guanosine 5'-diphosphate(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate trianion GDP GDP trianion guanosine 5'-diphosphate ChEBI 58189 Converted from EntitySet in Reactome Reactome DB_ID: 9764704 1 mature p21 RAS [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Kras [plasma membrane] Hras [plasma membrane] Nras [plasma membrane] UniProt P32883 UniProt Q61411 UniProt P08556 Reactome Database ID Release 78 9766393 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=9766393 Reactome R-MMU-109796 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=R-MMU-109796.1 Reactome DB_ID: 29438 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome DB_ID: 29420 1 Reactome DB_ID: 9764706 1 p21 RAS:GTP [plasma membrane] p21 RAS:GTP Converted from EntitySet in Reactome Reactome DB_ID: 9764704 1 Reactome DB_ID: 29438 1 Reactome Database ID Release 78 9764706 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=9764706 Reactome R-MMU-109783 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=R-MMU-109783.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9812311 GO 0005085 GO molecular function Reactome Database ID Release 78 9812549 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=9812549 Reactome Database ID Release 78 9812551 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=9812551 Reactome R-MMU-2424477 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=R-MMU-2424477.1 GRB2-bound SOS promotes the formation of active GTP-bound RAS. This activates the mitogen-activated protein kinase (MAPK) cascade, leading to cell growth and differentiation. 9690470 Pubmed 1998 The structural basis of the activation of Ras by Sos Boriack-Sjodin, PA Margarit, SM Bar-Sagi, Dafna Kuriyan, J Nature 394:337-43 inferred by electronic annotation IEA GO IEA Recruitment of GADS:SLP-76 to p-5Y-LAT Recruitment of GADS:SLP-76 to p-5Y-LAT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9812311 1 Reactome DB_ID: 9812302 1 GADS:SLP76 [cytosol] GADS:SLP76 Reactome DB_ID: 9771207 1 UniProt:O89100 Grap2 UniProt O89100 1 EQUAL 330 EQUAL Reactome DB_ID: 430203 1 UniProt:Q60787 Lcp2 Lcp2 Lcp2 FUNCTION Involved in T-cell antigen receptor mediated signaling.SUBUNIT Interacts with SHB. Interacts with PRAM1 (By similarity). Interacts with SLA (PubMed:10662792). Interacts with GRB2 (PubMed:7706237). Interacts with CBLB (PubMed:10646608). Interacts (via SH2 domain) with CD6 (via tyrosine phosphorylated C-terminus) (PubMed:16914752, PubMed:24584089). Interacts with FYB1 and the phosphorylated form of FYB2 (By similarity).TISSUE SPECIFICITY Highly expressed in spleen, thymus, and peripheral blood leukocytes.DOMAIN The SH2 domain mediates interaction with SHB.PTM Phosphorylated after T-cell receptor activation by ZAP70, ITK and TXK, which leads to the up-regulation of Th1 preferred cytokine IL-2. SYK-dependent phosphorylation is required for recruitment of PI3K signaling components (By similarity). UniProt Q60787 1 EQUAL 533 EQUAL Reactome Database ID Release 78 9812302 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=9812302 Reactome R-MMU-2424463 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=R-MMU-2424463.1 Reactome DB_ID: 9812313 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76 [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76 Reactome DB_ID: 9812311 1 Reactome DB_ID: 9812302 1 Reactome Database ID Release 78 9812313 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=9812313 Reactome R-MMU-2424464 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=R-MMU-2424464.1 Reactome Database ID Release 78 9812315 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=9812315 Reactome R-MMU-2396561 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=R-MMU-2396561.1 Gads/GRAP2 (GRB2-related adapter protein 2) is member of the GRB2 adaptor family with a central SH2 domain and linker region flanked by amino- and carboxy-terminal SH3 domains. SLP-76 associates constitutively via its central 20-amino acid proline-rich domain with the C-terminal SH3 domain of Gads, which recruits it to LAT following receptor stimulation. Upon LAT phosphorylation, Gads:SLP-76 complex principally binds to phosphorylated LAT tyrosine 191, with a reduced amount of binding to phosphorylated tyrosine 171 and no interaction with phosphorylated tyrosines 132 or 226 (Houtman et al. 2004, Zhu et al. 2003). Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways (Liu et al. 1999). The LAT-Gads-SLP-76 complex creates a platform for the recruitment of multiple signaling molecules, including PLCgamma1, GRB2, NCK, Rho GEFs, VAV and the Tec-family kinases ITK and BTK (Liu et al. 1999 & 2001, Asada et al. 1999, Yablonski et al. 2001). 11390650 Pubmed 2001 Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT Yablonski, D Kadlecek, T Weiss, A Mol Cell Biol 21:4208-18 12496416 Pubmed 2003 Minimal requirement of tyrosine residues of linker for activation of T cells in TCR signaling and thymocyte development Zhu, Minghua Janssen, Erin Zhang, Weiguo J. Immunol. 170:325-33 16467851 Pubmed 2006 Recruitment and activation of PLCgamma1 in T cells: a new insight into old domains Braiman, Alex Barda-Saad, Mira Sommers, Connie L Samelson, Lawrence E EMBO J. 25:774-84 10224278 Pubmed 1999 Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT Asada, H Ishii, N Sasaki, Y Endo, K Kasai, H Tanaka, N Takeshita, T Tsuchiya, S Konno, T Sugamura, K J. Exp. Med. 189:1383-90 10021361 Pubmed 1999 The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors Liu, S K Fang, N Koretzky, G A McGlade, C J Curr. Biol. 9:67-75 11607830 Pubmed 2001 The role of Gads in hematopoietic cell signalling Liu, SK Berry, DM McGlade, CJ Oncogene 20:6284-90 15065860 Pubmed 2004 Binding specificity of multiprotein signaling complexes is determined by both cooperative interactions and affinity preferences Houtman, Jon C D Higashimoto, Yuichiro Dimasi, Nazzareno Cho, Sangwoo Yamaguchi, Hiroshi Bowden, Brent Regan, Carole Malchiodi, Emilio L Mariuzza, Roy Schuck, Peter Appella, E Samelson, Lawrence E Biochemistry 43:4170-8 inferred by electronic annotation IEA GO IEA Recruitment of PLC-gamma to SLP-76 and p-5Y-LAT Recruitment of PLC-gamma to SLP-76 and p-5Y-LAT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9808191 1 PLC gamma1,2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Plcg1 [cytosol] Plcg2 [cytosol] UniProt Q62077 UniProt Q8CIH5 Reactome DB_ID: 9812313 1 Reactome DB_ID: 9812317 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCG [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCG Converted from EntitySet in Reactome Reactome DB_ID: 9808191 1 Reactome DB_ID: 9812313 1 Reactome Database ID Release 78 9812317 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=9812317 Reactome R-MMU-2396571 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=R-MMU-2396571.1 Reactome Database ID Release 78 9812327 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=9812327 Reactome R-MMU-2396606 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=R-MMU-2396606.1 The phospholipase PLC-gamma is an important mediator of TCR, FCERI and DAP12 signal transduction. PLC-gamma hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) and in-turn promotes the Ca+2 influx and activation of NFAT. Activation of PLC-gamma1 entails the binding of PLC-gamma1 to both LAT and SLP-76 adapter proteins. The amino-terminal SH2 domain of PLC-gamma1 was shown to preferentially bind phosphorylated LAT Y132 with high affinity and no detectable binding to phosphorylated tyrosines 171, 191, and 226. PLC-gamma1 was also shown to bind the adapter protein SLP-76 indirectly through GADS, which is bound to LAT at Y171 and Y191. SH3 domain of PLC-gamma1 associates with the proline-rich region of SLP-76 (Yablonski et al. 2001). PLC-gamma1 associates with Gads/SLP-76 complex before binding to p-Y132 of LAT (Houtman et al. 2005). PLC-gamma1 association with LAT is stabilized by Gads/SLP-76 bound to LAT (Zhu et al.2003). Association of PLC-gamma to LAT and SLP-76 couples it to the kinases (Syk and Tec family kinase) required for tyrosine phosphorylation and activation of PLC-gamma. <br>Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms, which are phosphorylated by BTK/ITK and/or SYK. FCERI-dependent Ca2+ release requires the recruitment of PLC-gamma by SLP-76 and LAT. In mast cells, increased intracellular calcium triggers rapid release of preformed mediators, through a process of vesicle exocytosis, known as degranulation.<br>Recruitment and activation of phospholipase C gamma (PLC-gamma) is involved in DAP12 signal transduction. Phosphorylation of multiple substrates including PLC-gamma1 has been observed in Ly49D/DAP12 triggered NK cells (McVicar et al. 1998). In myeloid cells, PLC-gamma2 is recruited and then phosphorylated upon activation of TREM2 and DAP12 (Peng et al. 2010). 20484116 Pubmed 2010 TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1 Peng, Qisheng Malhotra, Shikha Torchia, James A Kerr, William G Coggeshall, K Mark Humphrey, Mary Beth Sci Signal 3:ra38 12471105 Pubmed 2002 Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and Fc gamma R Wen, Renren Jou, Shiann-Tarng Chen, Yuhong Hoffmeyer, Angelica Wang, Demin J. Immunol. 169:6743-52 16081816 Pubmed 2005 Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways Houtman, Jon C D Houghtling, Richard A Barda-Saad, Mira Toda, Yoko Samelson, Lawrence E J. Immunol. 175:2449-58 9830044 Pubmed 1998 DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase McVicar, D W Taylor, L S Gosselin, P Willette-Brown, J Mikhael, A I Geahlen, R L Nakamura, M C Linnemeyer, P Seaman, W E Anderson, S K Ortaldo, J R Mason, L H J. Biol. Chem. 273:32934-42 12640123 Pubmed 2003 Structural requirements of SLP-76 in signaling via the high-affinity immunoglobulin E receptor (Fc epsilon RI) in mast cells Kettner, Alexander Pivniouk, Vadim Kumar, Lalit Falet, Hervé Lee, Jeng-Shin Mulligan, Richard Geha, Raif S Mol. Cell. Biol. 23:2395-406 inferred by electronic annotation IEA GO IEA 2.7.10 Phosphorylation of SLP-76 by p-SYK Phosphorylation of SLP-76 by p-SYK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 3 Reactome DB_ID: 9812317 1 Reactome DB_ID: 29370 3 Reactome DB_ID: 9812321 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG Converted from EntitySet in Reactome Reactome DB_ID: 9808191 1 Reactome DB_ID: 9812319 1 GADS:p-Y113,Y128,Y145-SLP-76 [cytosol] GADS:p-Y113,Y128,Y145-SLP-76 Reactome DB_ID: 9771207 1 1 EQUAL 330 EQUAL Reactome DB_ID: 9771217 1 O4'-phospho-L-tyrosine at 113 (in Homo sapiens) 113 EQUAL O4'-phospho-L-tyrosine at 128 (in Homo sapiens) 128 EQUAL O4'-phospho-L-tyrosine at 145 (in Homo sapiens) 145 EQUAL 1 EQUAL 533 EQUAL Reactome Database ID Release 78 9812319 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=9812319 Reactome R-MMU-2424466 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=R-MMU-2424466.1 Reactome DB_ID: 9812311 1 Reactome Database ID Release 78 9812321 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=9812321 Reactome R-MMU-2424460 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=R-MMU-2424460.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813910 Reactome Database ID Release 78 9813984 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=9813984 Reactome R-MMU-2730851 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=R-MMU-2730851.1 SLP-76 lacks intrinsic catalytic activity and acts as a scaffold, recruiting other proteins for correct localization during molecular signal transduction (Bogin et al. 2007). Activation of FCERI leads to tyrosine phosphorylation of SLP-76 (Gross et al. 1999). SLP-76 has three potential tyrosine phosphorylation sites within its amino terminus region: Y113, Y128, and Y145. Phosphorylation may be mediated by SYK, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996). 8702662 Pubmed 1996 Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function Bubeck Wardenburg, J Fu, C Jackman, JK Flotow, H Wilkinson, SE Williams, DH Johnson, R Kong, G Chan, AC Findell, PR J Biol Chem 271:19641-4 10026222 Pubmed 1999 Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets Gross, BS Lee, JR Clements, JL Turner, M Tybulewicz, VL Findell, PR Koretzky, GA Watson, SP J Biol Chem 274:5963-71 8995445 Pubmed 1997 SLP-76 is a substrate of the high affinity IgE receptor-stimulated protein tyrosine kinases in rat basophilic leukemia cells Hendricks-Taylor, L R Motto, D G Zhang, J Siraganian, R P Koretzky, G A J. Biol. Chem. 272:1363-7 17420479 Pubmed 2007 SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK Bogin, Yaron Ainey, Carmit Beach, Dvora Yablonski, Deborah Proc. Natl. Acad. Sci. U.S.A. 104:6638-43 19592646 Pubmed 2009 SLP-76 couples Syk to the osteoclast cytoskeleton Reeve, JL Zou, W Liu, Y Maltzman, JS Ross, FP Teitelbaum, SL J Immunol 183:1804-12 inferred by electronic annotation IEA GO IEA Recruitment of VAV to p-SLP-76 Recruitment of VAV to p-SLP-76 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9812321 1 Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 VAV1,2,3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Vav2 [cytosol] Vav3 [cytosol] Vav1 [cytosol] UniProt Q60992 UniProt Q9R0C8 UniProt P27870 Reactome DB_ID: 9813947 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV Reactome DB_ID: 9812321 1 Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 Reactome Database ID Release 78 9813947 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=9813947 Reactome R-MMU-2685668 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=R-MMU-2685668.1 Reactome Database ID Release 78 9814110 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=9814110 Reactome R-MMU-2730892 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=R-MMU-2730892.1 VAV an activator of RAC-GTPases, is redistributed to plasma membrane and is phosphorylated following engagement of FCERI. Phosphorylated SLP-76 tyrosines Y113 and Y128 (112Y and 128Y in mouse) provide binding sites for the SH2 domains of VAV. The binding of VAV to these phosphotyrosine residues may link SLP-76 to the Jun amino-terminal kinase (JNK) pathway and the actin cytoskeleton (Kettner et al. 2003).<br>In addition to its known role as guanine nucleotide exchange factor (GEF), VAV also modulates cytokine production in mast cells. VAV1-deficient bone marrow-derived mast cells exhibited reduced degranulation and cytokine production and calcium release in addition of reduced activation of c-Jun NH2-terminal kinase 1 (JNK1), although tyrosine phosphorylation of FCERI, SYK and LAT was normal (Manetz et al. 2001, Arudchandran et al. 2000, Song et al. 1999). 21659545 Pubmed 2011 Btk is a positive regulator in the TREM-1/DAP12 signaling pathway Ormsby, Tereza Schlecker, Eva Ferdin, Janina Tessarz, Anja Sibylle Angelisová, Pavla Köprülü, Afitap Derya Borte, Michael Warnatz, Klaus Schulze, Ilka Ellmeier, Wilfried Horejsí, Václav Cerwenka, Adelheid Blood 118:936-45 8673706 Pubmed 1996 Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation Wu, J Motto, DG Koretzky, GA Weiss, A Immunity 4:593-602 11340169 Pubmed 2001 Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells Manetz, T S Gonzalez-Espinosa, C Arudchandran, R Xirasagar, S Tybulewicz, V Rivera, J Mol. Cell. Biol. 21:3763-74 10395673 Pubmed 1999 Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway Song, J S Haleem-Smith, H Arudchandran, R Gomez, J Scott, P M Mill, J F Tan, T H Rivera, J J. Immunol. 163:802-10 10620604 Pubmed 2000 The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of c-Jun NH(2)-terminal kinase 1 Arudchandran, R Brown, M J Peirce, M J Song, J S Zhang, J Siraganian, R P Blank, U Rivera, J J. Exp. Med. 191:47-60 10934226 Pubmed 2000 The Rho family guanine nucleotide exchange factor Vav-2 regulates the development of cell-mediated cytotoxicity Billadeau, D D Mackie, S M Schoon, R A Leibson, P J J. Exp. Med. 192:381-92 inferred by electronic annotation IEA GO IEA Phosphorylation and activation of VAV Phosphorylation and activation of VAV This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9813947 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9813940 1 p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV [plasma membrane] p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV Reactome DB_ID: 9812321 1 Converted from EntitySet in Reactome Reactome DB_ID: 9808233 1 p-VAV family [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Vav2 [cytosol] phospho-Vav1 [cytosol] phospho-Vav3 [cytosol] Reactome Database ID Release 78 9813940 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=9813940 Reactome R-MMU-2685666 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=R-MMU-2685666.1 Reactome Database ID Release 78 9813949 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=9813949 Reactome R-MMU-2730841 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=R-MMU-2730841.1 Phosphorylation of VAV stimulates its GEF activity for RAC1, and thus it plays an important role in linking FCERI to the RAC1-JNK pathway. VAV exists in an auto-inhibitory state, folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the calponin homology (CH) domain to the C1 region. Activation of VAV may involve three events which relieve this auto-inhibition: phosphorylation of tyrosines in the acidic domain causes them to be displaced from the DH domain; binding of a ligand to the CH domain may cause it to release the C1 domain; binding of the PI3K product PIP3 to the PH domain may alter its conformation (Aghazadeh et al. 2000). VAV is phosphorylated on tyrosine residue (Y174 in VAV1/172 in VAV2/173 in VAV3) in the acidic domain. This is mediated by SYK and Src-family tyrosine kinases (Deckert et al. 1996, Schuebel et al. 1998). Once activated, VAV is involved in the activation of RAC1, PAK1, MEK and ERK and cytokine production. 11007481 Pubmed 2000 Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation Aghazadeh, B Lowry, WE Huang, XY Rosen, MK Cell 102:625-33 9099726 Pubmed 1997 Tyrosine phosphorylation of the vav proto-oncogene product links FcepsilonRI to the Rac1-JNK pathway Teramoto, H Salem, P Robbins, K C Bustelo, X R Gutkind, J S J. Biol. Chem. 272:10751-5 8986718 Pubmed 1996 Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product Deckert, M Tartare-Deckert, S Couture, C Mustelin, T Altman, A Immunity 5:591-604 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 78 8951567 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=8951567 Reactome R-HSA-8951567 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=R-HSA-8951567.1 Reactome DB_ID: 179838 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate PIP3 ChEBI 16618 Activation of RAC1 by VAV Activation of RAC1 by VAV This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9779609 1 RAC1:GDP [cytosol] RAC1:GDP Reactome DB_ID: 9779607 1 UniProt:P63001 Rac1 Rac1 Rac1 FUNCTION Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states (PubMed:24352656). In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles. Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity. In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. In glioma cells, promotes cell migration and invasion. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. In neurons, is involved in dendritic spine formation and synaptic plasticity (PubMed:24352656, PubMed:26969129). In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX (PubMed:12695502). In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization (By similarity).ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. GTP hydrolysis is stimulated by ARHGAP30 and ARHGAP44.SUBUNIT Interacts with the GEF proteins PREX1, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with BAIAP2, BAIAP2L1, PLXNB1, CYFIP1/SRA-1 and DEF6. Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM; the interaction requires PAK1. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ITGB4. Interacts with the GTP-bound form of RAB7A. Interacts with ARHGEF2. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with NOXA1. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts with PACSIN2. Interacts with ITGB1BP1 (By similarity). Interacts with the GEF protein RASGRF2, which promotes the exchange between GDP and GTP, and therefore activates it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a complex with MAP2K3, MAP3K3 and CCM2. Interacts with NISCH. Interacts with PIP5K1A. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with SRGAP2. Interacts with PLXNB3. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (By similarity). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation. Interacts (GTP-bound form) with SH3RF3. Interacts with PAK2 (By similarity). Interacts (GTP-bound form) with SH3RF1 (PubMed:22959435). Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1 (PubMed:23963642). Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (By similarity). Interacts (GTP-bound form preferentially) with CYRIB (By similarity). Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1 (By similarity). Interacts with GARRE1 (By similarity).TISSUE SPECIFICITY Widely expressed.DEVELOPMENTAL STAGE Expressed in the neocortical neurons in the developing brain.DOMAIN The effector region mediates interaction with DEF6.PTM GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.DISRUPTION PHENOTYPE Conditional knockout of Rac1 in the telencephalic ventricular zone of embryos leads to primary microcephaly. Self-renewal, survival, and differentiation of telencephalic neural progenitor cells is affected.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P63001 1 EQUAL 189 EQUAL Reactome DB_ID: 29420 1 Reactome Database ID Release 78 9779609 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=9779609 Reactome R-MMU-445010 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=R-MMU-445010.1 Reactome DB_ID: 9813940 1 Reactome DB_ID: 29438 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 9813942 1 p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP [plasma membrane] p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP Reactome DB_ID: 9812321 1 Reactome DB_ID: 179838 1 Reactome DB_ID: 2316458 1 Rac1:GTP [plasma membrane] Rac1:GTP Reactome DB_ID: 2316449 1 1 EQUAL 189 EQUAL Reactome DB_ID: 29438 1 Reactome Database ID Release 78 2316458 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=2316458 Reactome R-MMU-2316458 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=R-MMU-2316458.1 Converted from EntitySet in Reactome Reactome DB_ID: 9808233 1 Reactome Database ID Release 78 9813942 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=9813942 Reactome R-MMU-2685706 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=R-MMU-2685706.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813940 Reactome Database ID Release 78 9813943 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=9813943 Reactome Database ID Release 78 9813945 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=9813945 Reactome R-MMU-2730840 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=R-MMU-2730840.1 Rac1 exists in inactive state in the cytosol until the reception of extracellular signals by the cell. To be functional Rac1 is rapidly targeted to the plasma membrane upon cell stimulation. The main factors involved in this mobilisation are the Rac GEFs like VAV and phospholipids (PtdIns(4,5)P2, PtdIns(3,4,5) P3) and lipid rafts at the plasma membrane. VAV catalyses the disassociation of GDP from Rac1 by modifying the nucleotide-binding site such that GDP is released and subsequently replaced. The incoming GTP occupies the nucleotide binding site and finally displaces VAV from Rac1 (Bos et al. 2007, Bustelo et al. 2012). 17540168 Pubmed 2007 GEFs and GAPs: critical elements in the control of small G proteins Bos, Johannes L Rehmann, Holger Wittinghofer, A Cell 129:865-77 22714419 Pubmed 0 Rac-ing to the plasma membrane: the long and complex work commute of Rac1 during cell signaling Bustelo, Xosé R Ojeda, Virginia Barreira, María Sauzeau, Vincent Castro-Castro, Antonio Small GTPases 3:60-6 12670394 Pubmed 2003 Vav1: a key signal transducer downstream of the TCR Tybulewicz, VL Ardouin, L Prisco, A Reynolds, LF Immunol Rev 192:42-52 inferred by electronic annotation IEA GO IEA Recruitment of PAK to the membrane by binding active RAC1 Recruitment of PAK to the membrane by binding active RAC1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9813986 1 PAK dimer [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 9813942 1 Reactome DB_ID: 9813988 1 p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP:PAK dimer [plasma membrane] p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP:PAK dimer Reactome DB_ID: 9813942 1 Converted from EntitySet in Reactome Reactome DB_ID: 9813986 1 Reactome Database ID Release 78 9813988 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=9813988 Reactome R-MMU-2685694 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=R-MMU-2685694.1 Reactome Database ID Release 78 9814108 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=9814108 Reactome R-MMU-2730889 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=R-MMU-2730889.1 PAK1 kinase is a member of serine/threonine protein kinase family and is widely believed as mediator between Cdc42 and Rac1 and the JNK signal transduction pathway. PAK1 is involved in regulating FCERI mediated mast cell degranulation via effects on calcium mobilisation and cytoskeletal changes (Allen et al. 2009). The conventional PAK family contains a N-terminal conserved Cdc42/Rac-interacting binding domain (CRIB) that overlaps a kinase inhibitory (KI) domain and a C-terminal catalytic domain. PAK1 molecules form trans-inhibited homodimers in which the N-terminal kinase inhibitory (KI) domain of one PAK1 molecule in the dimer binds and inhibits the C-terminal catalytic domain of the other. Isoprenylated Rac1/Cdc42-GTP localized to the membrane recruits PAK1 by binding to the N-terminal CRIB domain. Binding of activated Cdc42/Rac1, breaks the PAK1-dimer and removes the trans-inhibition and stimulates serine/threonine kinase activity of that allows autophosphorylation (Lu & Mayer 1999, Parrini et all. 2009, Zhao et al. 2005). 19574218 Pubmed 2009 Dissecting activation of the PAK1 kinase at protrusions in living cells Parrini, Maria Carla Camonis, J Matsuda, Michiyuki de Gunzburg, Jean J. Biol. Chem. 284:24133-43 19124833 Pubmed 2009 p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics Allen, Jayme D Jaffer, Zahara M Park, Su-Jung Burgin, Sarah Hofmann, Clemens Sells, Mary Ann Chen, Shi Derr-Yellin, Ethel Michels, Elizabeth G McDaniel, Andrew Bessler, Waylan K Ingram, David A Atkinson, Simon J Travers, Jeffrey B Chernoff, J Clapp, D Wade Blood 113:2695-705 9989831 Pubmed 1999 Mechanism of activation of Pak1 kinase by membrane localization Lu, W Mayer, B J Oncogene 18:797-806 15548136 Pubmed 2005 PAK and other Rho-associated kinases--effectors with surprisingly diverse mechanisms of regulation Zhao, ZS Manser, E Biochem J 386:201-14 inferred by electronic annotation IEA GO IEA 2.7.11 Autophosphorylation of PAK Autophosphorylation of PAK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 4 Reactome DB_ID: 9813988 1 Reactome DB_ID: 29370 4 Reactome DB_ID: 9813942 1 Converted from EntitySet in Reactome Reactome DB_ID: 9813990 2 p-2Y-PAK [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Pak2 [cytosol] phospho-Pak1 [cytosol] UniProt Q8CIN4 UniProt O88643 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813988 GO 0004674 GO molecular function Reactome Database ID Release 78 9813991 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=9813991 Reactome Database ID Release 78 9813993 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=9813993 Reactome R-MMU-2730856 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=R-MMU-2730856.1 Upon dimer disassociation PAK1 autophosphorylates in both cis- and trans- manner. Serine 144 (S144) in the GTPase-binding domain and threonine 423 (T423) in the activation loop are the target sites for autophosphorylation (Parrini et al. 2002). 11804587 Pubmed 2002 Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1 Parrini, MC Lei, M Harrison, SC Mayer, BJ Mol Cell 9:73-83 11278486 Pubmed 2001 The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity Chong, C Tan, L Lim, L Manser, E J Biol Chem 276:17347-53 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of MEK4 by MEKK1 Phosphorylation of MEK4 by MEKK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9785417 1 UniProt:P47809 Map2k4 Map2k4 Map2k4 Prkmk4 Mkk4 Mek4 Serk1 Skk1 Jnkk1 Sek1 FUNCTION Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.ACTIVITY REGULATION Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.SUBUNIT Interacts with SPAG9. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14 (By similarity). Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3 (By similarity).TISSUE SPECIFICITY Strong expression is detected in most of the central nervous system and in liver and thymus during early stages of development. While expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of expression in the central nervous system persists throughout postnatal development and remained at a stable level in adult brain.DOMAIN The DVD domain (residues 362-385) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation (By similarity).DOMAIN The D domain (residues 35-50) contains a conserved docking site and is required for the binding to MAPk substrates.PTM Activated by phosphorylation on Ser-255 and Thr-259 by MAP kinase kinase kinases (MAP3Ks).DISRUPTION PHENOTYPE Causes irregular alignment of Purkinje cells in the cerebellum and delayed radial migration in the cortex during brain development. The cardiac-specific deletion prevents pathological cardiac hypertrophy.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. UniProt P47809 1 EQUAL 399 EQUAL Reactome DB_ID: 29370 2 Reactome DB_ID: 9764006 1 O-phospho-L-serine at 257 (in Homo sapiens) 257 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at 261 (in Homo sapiens) 261 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 399 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9814084 UniProt:P53349 Map3k1 Map3k1 Map3k1 Mekk1 Mekk FUNCTION Component of a protein kinase signal transduction cascade (PubMed:14500727). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:14500727). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:14500727).ACTIVITY REGULATION Activated by autophosphorylation on Thr-1381 and Thr-1393 following oligomerization.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes through its N-terminus. Oligomerizes after binding MAP4K2 or TRAF2. Interacts with AXIN1. Interacts (via the kinase catalytic domain) with STK38 (By similarity). Interacts with GRIPAP1 (By similarity).TISSUE SPECIFICITY Highly expressed in the heart and spleen while a lower level expression is seen in the liver.PTM Autophosphorylated.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt P53349 O-phospho-L-threonine at 1400 (in Homo sapiens) 1400 EQUAL O-phospho-L-threonine at 1412 (in Homo sapiens) 1412 EQUAL 2 EQUAL 1512 EQUAL Reactome Database ID Release 78 9814085 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=9814085 Reactome Database ID Release 78 9814114 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=9814114 Reactome R-MMU-2730896 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=R-MMU-2730896.1 Activated MEKK1 then phosphorylates and activates SAPK/Erk kinase (SEK1), also known as MKK4 or Jun kinase kinase (JNKK) on serine and threonine residues at positions 257 and 261, respectively. 7997270 Pubmed 1994 Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 Yan, M Dai, T Deak, J C Kyriakis, J M Zon, L I Woodgett, J R Templeton, D J Nature 372:798-800 7855889 Pubmed 1994 MAPKs: new JNK expands the group Davis, RJ Trends Biochem. Sci. 19:470-3 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of MEK7 by MEKK1 Phosphorylation of MEK7 by MEKK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9785415 1 UniProt:Q8CE90 Map2k7 UniProt Q8CE90 2 EQUAL 419 EQUAL Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 9764001 1 O-phospho-L-serine at 271 (in Homo sapiens) 271 EQUAL O-phospho-L-threonine at 275 (in Homo sapiens) 275 EQUAL 1 EQUAL 419 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9814084 O-phospho-L-threonine at 1400 (in Homo sapiens) 1400 EQUAL O-phospho-L-threonine at 1412 (in Homo sapiens) 1412 EQUAL 2 EQUAL 1512 EQUAL Reactome Database ID Release 78 9814087 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=9814087 Reactome R-MMU-2730868 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=R-MMU-2730868.1 MKK7 is activated by MEKK1 and the residues serine 271 and threonine 275 are the potential phosphorylation sites that are crucial for its kinase activity (phosphorylation sites are based on sequence alignment with MAP kinase kinase family members). 11306453 Pubmed 2001 Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers Kim, H L Vander Griend, D J Yang, X Benson, D A Dubauskas, Z Yoshida, B A Chekmareva, M A Ichikawa, Y Sokoloff, M H Zhan, P Karrison, T Lin, A Stadler, W M Ichikawa, T Rubin, M A Rinker-Schaeffer, C W Cancer Res. 61:2833-7 9639556 Pubmed 1998 Differential activation of stress-activated protein kinase kinases SKK4/MKK7 and SKK1/MKK4 by the mixed-lineage kinase-2 and mitogen-activated protein kinase kinase (MKK) kinase-1 Cuenda, A Dorow, D S Biochem. J. 333:11-5 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of human JNKs by activated MKK4/MKK7 Phosphorylation of human JNKs by activated MKK4/MKK7 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Converted from EntitySet in Reactome Reactome DB_ID: 9763987 1 MAPK8,9,10 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Mapk10 [cytosol] Mapk8 [cytosol] Mapk9 [cytosol] UniProt Q61831 UniProt Q91Y86 UniProt Q9WTU6 Reactome DB_ID: 29370 2 Converted from EntitySet in Reactome Reactome DB_ID: 9763995 1 p-MAPK8,9,10 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Mapk10 [cytosol] phospho-Mapk8 [cytosol] phospho-Mapk9 [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9764008 p-MAP2K4/p-MAP2K7 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Map2k7 [cytosol] phospho-Map2k4 [cytosol] GO 0008545 GO molecular function Reactome Database ID Release 78 9764009 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=9764009 Reactome Database ID Release 78 9764011 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=9764011 Reactome R-MMU-168162 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=R-MMU-168162.1 Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. <p>JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183). 11062067 Pubmed 2000 Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 Fleming, Y Armstrong, CG Morrice, N Paterson, A Goedert, M Cohen, P Biochem J 352:145-54 18713996 Pubmed 2008 Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases Yoshizawa, T Hammaker, D Sweeney, SE Boyle, DL Firestein, GS J Immunol 181:3252-8 13130464 Pubmed 2003 Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK Sundarrajan, M Boyle, DL Chabaud-Riou, M Hammaker, D Firestein, GS Arthritis Rheum 48:2450-60 16186825 Pubmed 2005 Essential function for the kinase TAK1 in innate and adaptive immune responses Sato, S Sanjo, H Takeda, K Ninomiya-Tsuji, J Yamamoto, M Kawai, T Matsumoto, K Takeuchi, O Akira, Shizuo Nat Immunol 6:1087-95 17875933 Pubmed 2007 Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death Wang, X Nadarajah, B Robinson, AC McColl, BW Jin, JW Dajas-Bailador, F Boot-Handford, RP Tournier, C Mol Cell Biol 27:7935-46 9162092 Pubmed 1997 Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. Deacon, K Blank, JL J Biol Chem 272:14489-96 inferred by electronic annotation IEA GO IEA Activated human JNKs migrate to nucleoplasm Activated human JNKs migrate to nucleoplasm This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9763995 1 Converted from EntitySet in Reactome Reactome DB_ID: 9763896 1 nucleoplasm GO 0005654 p-MAPK8,9,10 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Mapk9 [nucleoplasm] phospho-Mapk10 [nucleoplasm] phospho-Mapk8 [nucleoplasm] Reactome Database ID Release 78 9785431 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=9785431 Reactome R-MMU-450348 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=R-MMU-450348.1 c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors. 9195981 Pubmed 1997 A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. Mizukami, Y Yoshioka, K Morimoto, S Yoshida, K J Biol Chem 272:16657-62 12193592 Pubmed 2002 Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP) Lutz, C Nimpf, J Jenny, M Boecklinger, K Enzinger, C Utermann, G Baier-Bitterlich, G Baier, G J Biol Chem 277:43143-51 inferred by electronic annotation IEA GO IEA 2.7.11 Activated JNKs phosphorylate c-JUN Activated JNKs phosphorylate c-JUN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29358 2 Reactome DB_ID: 9763906 1 UniProt:P05627 Jun Jun Jun FUNCTION Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3' (PubMed:14707112). Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation (PubMed:17210646). Involved in activated KRAS-mediated transcriptional activation of USP28 (By similarity). Binds to the USP28 promoter (By similarity).SUBUNIT Heterodimer with either FOS or BATF3 or ATF7 (By similarity). The ATF7/JUN heterodimer is essential for ATF7 transactivation activity. Interacts with SP1, SPIB and TCF20. Interacts with COPS5; the interaction leads indirectly to its phosphorylation. Component of the SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site. The SMAD3/SMAD4 heterodimer acts synergistically with the JUN/FOS heterodimer to activate transcription in response to TGF-beta (By similarity). Interacts (via its basic DNA binding and leucine zipper domains) with SMAD3 (via an N-terminal domain); the interaction is required for TGF-beta-mediated transactivation of the SMAD3/SMAD4/JUN/FOS/complex (By similarity). Interacts with DSIPI; the interaction inhibits the binding of active AP1 to its target DNA (PubMed:11397794). Interacts with HIVEP3 and MYBBP1A (PubMed:9447996, PubMed:14707112). Interacts with methylated RNF187 (PubMed:20852630). Binds to HIPK3. Interacts (when phosphorylated) with FBXW7 (By similarity). Interacts with PRR7 (PubMed:27458189). Found in a complex with PRR7 and FBXW7 (By similarity). Interacts with PRR7 and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (By similarity). Interacts with RBM39 (PubMed:11704680). Interacts with PAGE4 (By similarity).PTM Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances the transcriptional activity. Phosphorylated by HIPK3. Phosphorylated by DYRK2 at Ser-246; this primes the protein for subsequent phosphorylation by GSK3B at Thr-242. Phosphorylated at Thr-242, Ser-246 and Ser-252 by GSK3B; phosphorylation reduces its ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-89, Thr-93 and Thr-289 thereby promoting JUN-mediated cell proliferation and transformation. Phosphorylated by PLK3 following hypoxia or UV irradiation, leading to increase DNA-binding activity (By similarity).PTM Ubiquitinated by the SCF(FBXW7), leading to its degradation. Ubiquitination takes place following phosphorylation, that promotes interaction with FBXW7.PTM Acetylated at Lys-271 by EP300.SIMILARITY Belongs to the bZIP family. Jun subfamily. UniProt P05627 1 EQUAL 331 EQUAL Reactome DB_ID: 9763908 1 O-phospho-L-serine at 63 63 EQUAL O-phospho-L-serine at 73 73 EQUAL 1 EQUAL 331 EQUAL Reactome DB_ID: 113582 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9763896 GO 0004705 GO molecular function Reactome Database ID Release 78 9763909 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=9763909 Reactome Database ID Release 78 9763911 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=9763911 Reactome R-MMU-168136 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=R-MMU-168136.1 JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus. 9561845 Pubmed 1998 Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development Ip, YT Davis, RJ Curr Opin Cell Biol 10:205-19 18793328 Pubmed 2008 c-Jun expression, activation and function in neural cell death, inflammation and repair Raivich, G J Neurochem 107:898-906 10871633 Pubmed 2000 c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity Dennler, S Prunier, C Ferrand, N Gauthier, JM Atfi, A J Biol Chem 275:28858-65 inferred by electronic annotation IEA GO IEA 2.7.11 c-FOS activation by phospho ERK1/2 c-FOS activation by phospho ERK1/2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29358 4 Reactome DB_ID: 9785400 1 UniProt:P01101 Fos UniProt P01101 1 EQUAL 380 EQUAL Reactome DB_ID: 9785377 1 O-phospho-L-serine at 362 (in Homo sapiens) 362 EQUAL O-phospho-L-serine at 374 (in Homo sapiens) 374 EQUAL O-phospho-L-threonine at 325 (in Homo sapiens) 325 EQUAL O-phospho-L-threonine at 331 (in Homo sapiens) 331 EQUAL 1 EQUAL 380 EQUAL Reactome DB_ID: 113582 4 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9769091 p-T,Y MAPK dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 78 9769092 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=9769092 Reactome Database ID Release 78 9785402 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=9785402 Reactome R-MMU-450325 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=R-MMU-450325.1 The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity. <p>On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.</p><p>Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover. 7588633 Pubmed 1995 The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells Okazaki, K Sagata, N EMBO J 14:5048-59 12134156 Pubmed 2002 Molecular interpretation of ERK signal duration by immediate early gene products Murphy, LO Smith, Stuart Chen, RH Fingar, DC Blenis, J Nat Cell Biol 4:556-64 inferred by electronic annotation IEA GO IEA Formation of Activated Protein 1 (AP-1) complex. cFOS/c-JUN heterodimer. Formation of Activated Protein 1 (AP-1) complex. cFOS/c-JUN heterodimer. This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9763908 1 O-phospho-L-serine at 63 63 EQUAL O-phospho-L-serine at 73 73 EQUAL 1 EQUAL 331 EQUAL Reactome DB_ID: 9785377 1 O-phospho-L-serine at 362 (in Homo sapiens) 362 EQUAL O-phospho-L-serine at 374 (in Homo sapiens) 374 EQUAL O-phospho-L-threonine at 325 (in Homo sapiens) 325 EQUAL O-phospho-L-threonine at 331 (in Homo sapiens) 331 EQUAL 1 EQUAL 380 EQUAL Reactome DB_ID: 9785379 1 p-2S-cJUN:p-2S,2T-cFOS [nucleoplasm] p-2S-cJUN:p-2S,2T-cFOS Reactome DB_ID: 9763908 1 O-phospho-L-serine at 63 63 EQUAL O-phospho-L-serine at 73 73 EQUAL 1 EQUAL 331 EQUAL Reactome DB_ID: 9785377 1 O-phospho-L-serine at 362 (in Homo sapiens) 362 EQUAL O-phospho-L-serine at 374 (in Homo sapiens) 374 EQUAL O-phospho-L-threonine at 325 (in Homo sapiens) 325 EQUAL O-phospho-L-threonine at 331 (in Homo sapiens) 331 EQUAL 1 EQUAL 380 EQUAL Reactome Database ID Release 78 9785379 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=9785379 Reactome R-MMU-450327 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=R-MMU-450327.1 Reactome Database ID Release 78 9785381 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=9785381 Reactome R-MMU-450292 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=R-MMU-450292.1 The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995). 7816143 Pubmed 1995 Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA Glover, JN Harrison, SC Nature 373:257-61 9030721 Pubmed 1997 Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents Ainbinder, E Bergelson, S Pinkus, R Daniel, V Eur J Biochem 243:49-57 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9860852 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=9860852 Reactome R-MMU-2871796 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=R-MMU-2871796.1 Formation of the LAT signaling complex leads to activation of MAPK and production of cytokines. The sequence of events that leads from LAT to cytokine production has not been as clearly defined as the sequence that leads to degranulation. However, the pathways that lead to cytokine production require the guanine-nucleotide-exchange factors SOS and VAV that regulate GDP-GTP exchange of RAS. After its activation, RAS positively regulates the RAF-dependent pathway that leads to phosphorylation and, in part, activation of the mitogen-activated protein kinases (MAPKs) extracellular-signal-regulated kinase 1 (ERK1) and ERK2 (Gilfillan & Tkaczyk 2006). 19290926 Pubmed 2009 The tyrosine kinase network regulating mast cell activation Gilfillan, Alasdair M Rivera, Juan Immunol. Rev. 228:149-69 17122878 Pubmed 2006 Intracellular signaling pathways in IgE-dependent mast cell activation Kope?, Agnieszka Panaszek, Bernard Fal, Andrzej M Arch. Immunol. Ther. Exp. (Warsz.) 54:393-401 17420272 Pubmed 2007 LAT and NTAL mediate immunoglobulin E-induced sustained extracellular signal-regulated kinase activation critical for mast cell survival Yamasaki, Sho Ishikawa, Eri Sakuma, Machie Kanagawa, Osami Cheng, Alec M Malissen, Bernard Saito, Takashi Mol. Cell. Biol. 27:4406-15 16470226 Pubmed 2006 Integrated signalling pathways for mast-cell activation Gilfillan, Alasdair M Tkaczyk, Christine Nat. Rev. Immunol. 6:218-30 inferred by electronic annotation IEA GO IEA FCERI mediated Ca+2 mobilization FCERI mediated Ca+2 mobilization This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.10 Phosphorylation of TEC kinases by p-SYK Phosphorylation of TEC kinases by p-SYK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9813895 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:TEC kinases:PIP3 [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:TEC kinases:PIP3 Converted from EntitySet in Reactome Reactome DB_ID: 9813893 1 TEC,BTK,ITK,(TXK) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Btk [cytosol] Itk [cytosol] Tec [cytosol] UniProt P35991 UniProt Q03526 UniProt P24604 Reactome DB_ID: 9812321 1 Reactome DB_ID: 179838 1 Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 Reactome Database ID Release 78 9813895 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=9813895 Reactome R-MMU-2685683 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=R-MMU-2685683.1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9813908 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3 [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3 Converted from EntitySet in Reactome Reactome DB_ID: 9813906 1 p-TEC kinases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Itk [cytosol] phospho-Tec [cytosol] p-Y551-Btk [cytosol] Reactome DB_ID: 9812321 1 Reactome DB_ID: 179838 1 Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 Reactome Database ID Release 78 9813908 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=9813908 Reactome R-MMU-2685675 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=R-MMU-2685675.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813910 Reactome Database ID Release 78 9813913 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=9813913 Reactome R-MMU-2730833 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=R-MMU-2730833.1 BTK/ITK are activated in a two step model. In the first step they are recruited to the membrane by binding to PIP3 or, alternatively with other binding partners like SLP-76. Once at the membrane SYK or Src-kinases in the vicinity phosphorylates Y551 (Y512 in ITK) in the activation loop of the catalytic domain of BTK to fully activate it (Rawlings et al. 1996, Park et al. 1996, Kawakami et al. 1994). 7518558 Pubmed 1994 Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking Kawakami, Y Yao, L Miura, T Tsukada, S Witte, O N Kawakami, T Mol. Cell. Biol. 14:5108-13 8629002 Pubmed 1996 Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases Rawlings, D J Scharenberg, A M Park, H Wahl, M I Lin, S Kato, R M Fluckiger, A C Witte, O N Kinet, J P Science 271:822-5 12573241 Pubmed 2003 Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases Nore, Beston F Mattsson, Pekka T Antonsson, Per Bäckesjö, Carl-Magnus Westlund, Anna Lennartsson, Johan Hansson, Henrik Löw, Peter Rönnstrand, Lars Smith, C I Edvard Biochim. Biophys. Acta 1645:123-32 8630736 Pubmed 1996 Regulation of Btk function by a major autophosphorylation site within the SH3 domain Park, H Wahl, M I Afar, D E Turck, C W Rawlings, D J Tam, C Scharenberg, A M Kinet, J P Witte, O N Immunity 4:515-25 inferred by electronic annotation IEA GO IEA 2.7.10 Autophosphorylation of BTK/ITK Autophosphorylation of BTK/ITK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 1 Reactome DB_ID: 9813908 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9814006 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinases [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinases Converted from EntitySet in Reactome Reactome DB_ID: 9814004 1 p-2Y-TEC kinases [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Tec [cytosol] p-Y551,Y223-Btk [cytosol] phospho-Itk [cytosol] Reactome DB_ID: 9812321 1 Reactome DB_ID: 179838 1 Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 Reactome Database ID Release 78 9814006 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=9814006 Reactome R-MMU-2685650 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=R-MMU-2685650.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813908 Reactome Database ID Release 78 9814007 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=9814007 Reactome Database ID Release 78 9814009 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=9814009 Reactome R-MMU-2730858 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=R-MMU-2730858.1 After initial phosphorylation by SFK's, subsequently Y223 (Y180 in ITK and Y206 in TEC) in the SH3 domain of BTK is autophosphorylated, which may prevent inhibitory intramolecular interactions (Nore et al. 2003, Joseph et al. 2007, Park et al. 1996) 17897671 Pubmed 2007 Mechanism and functional significance of Itk autophosphorylation Joseph, Raji E Fulton, D Bruce Andreotti, Amy H J. Mol. Biol. 373:1281-92 inferred by electronic annotation IEA GO IEA 3.1.4.11 Hydrolysis of PIP2 by PLCG Hydrolysis of PIP2 by PLCG This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 179856 1 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI 18348 Reactome DB_ID: 114520 1 1D-myo-inositol 1,4,5-trisphosphate [ChEBI:16595] 1D-myo-inositol 1,4,5-trisphosphate ChEBI 16595 Reactome DB_ID: 112275 1 diglyceride [ChEBI:18035] diglyceride ChEBI 18035 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813966 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3 [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3 Converted from EntitySet in Reactome Reactome DB_ID: 9813906 1 Reactome DB_ID: 9812575 1 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:p-PLCG [plasma membrane] p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:p-PLCG Reactome DB_ID: 9812319 1 Converted from EntitySet in Reactome Reactome DB_ID: 9812573 1 p-4Y-PLCG [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Plcg1 [plasma membrane] phospho-Plcg2 [plasma membrane] Reactome DB_ID: 9812311 1 Reactome Database ID Release 78 9812575 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=9812575 Reactome R-MMU-2685659 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=R-MMU-2685659.1 Reactome DB_ID: 179838 1 Converted from EntitySet in Reactome Reactome DB_ID: 9783413 1 Reactome Database ID Release 78 9813966 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=9813966 Reactome R-MMU-2685707 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=R-MMU-2685707.1 GO 0004435 GO molecular function Reactome Database ID Release 78 9813967 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=9813967 Reactome Database ID Release 78 9813969 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=9813969 Reactome R-MMU-2730847 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=R-MMU-2730847.1 Phosphoinositol 4,5-bisphosphate (PIP2) is cleaved in to two most important second messengers diacylglycerol (DAG) and Inositol 1,4,5-triphosphate (IP3) by phospholipase C (PLC). DAG remains within the membrane and activates protein kinase C (PKC) while IP3 leaves the cell membrane and binds to IP3 receptor that releases Ca2+ from endoplasmic reticulum (ER). 11395409 Pubmed 2001 Regulation of phosphoinositide-specific phospholipase C Rhee, S G Annu. Rev. Biochem. 70:281-312 inferred by electronic annotation IEA GO IEA Activation of Calcineurin Activation of Calcineurin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 74016 4 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 Reactome DB_ID: 2025905 1 Calmodulin:Calcium [cytosol] Calmodulin:Calcium Reactome DB_ID: 9016924 1 UniProt:P0DP26 Calm1 Calm1 Calm Cam1 Cam Calm1 FUNCTION Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis. Is a regulator of voltage-dependent L-type calcium channels. Mediates calcium-dependent inactivation of CACNA1C. Positively regulates calcium-activated potassium channel activity of KCNN2. Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding. Acts as a sensor to modulate the endomplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2 (By similarity).SUBUNIT Interacts with CEP97, CCP110, MYO1C, TTN/titin and SRY. Interacts with MYO10. Interacts with RRAD (By similarity). Interacts with USP6; the interaction is calcium dependent (By similarity). Interacts with CDK5RAP2. Interacts with SCN5A (By similarity). Interacts with FCHO1. Interacts with MIP in a 1:2 stoichiometry; the interaction with the cytoplasmic domains from two MIP subunits promotes MIP water channel closure. Interacts with ORAI1; this may play a role in the regulation of ORAI1-mediated calcium transport (By similarity). Interacts with RYR1 (PubMed:18650434). Interacts with MYO5A (PubMed:17151196). Interacts with IQCF1 (PubMed:25380116). Interacts with SYT7 (PubMed:24569478). Interacts with CEACAM1 (via cytoplasmic domain); this interaction is in a calcium dependent manner and reduces homophilic cell adhesion through dissociation of dimer (By similarity). Interacts with RYR2; regulates RYR2 calcium-release channel activity (PubMed:18650434). Interacts with PCP4; regulates calmodulin calcium-binding (By similarity). Interacts with the heterotetrameric KCNQ2 and KCNQ3 channel; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel (By similarity). Interacts with alpha-synuclein/SNCA (By similarity). Interacts with SLC9A1 in a calcium-dependent manner (By similarity). In the absence of Ca(+2), interacts with GIMAP4 (via IQ domain) (PubMed:16569770). Interacts with SCN8A; the interaction modulates the inactivation rate of SCN8A (PubMed:23942337). Interaction with KIF1A; the interaction is increased in presence of calcium and increases neuronal dense core vesicles motility (By similarity). Interacts with KCNN3 (By similarity). Interacts with KCNQ1 (via C-terminus); forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner (By similarity). Interacts with PIK3C3; the interaction modulates PIK3C3 kinase activity (By similarity).DOMAIN The N-terminal and C-terminal lobes of CALM bind to the C-terminus of KCNQ1 in a clamp-like conformation. Binding of CALM C-terminus to KCNQ1 is calcium-independent but is essential for assembly of the structure. Binding of CALM N-terminus to KCNQ1 is calcium-dependent and regulates electrophysiological activity of the channel.PTM Ubiquitination results in a strongly decreased activity.PTM Phosphorylation results in a decreased activity.MISCELLANEOUS This protein has four functional calcium-binding sites.SIMILARITY Belongs to the calmodulin family. UniProt P0DP26 2 EQUAL 149 EQUAL Reactome DB_ID: 74016 4 Reactome Database ID Release 78 2025905 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=2025905 Reactome R-MMU-2025905 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=R-MMU-2025905.2 Reactome DB_ID: 9808011 1 Calcineurin (CaN) [cytosol] Calcineurin (CaN) Reactome DB_ID: 9808009 1 PPP3CA,B:Fe3+:Zn2+ [cytosol] PPP3CA,B:Fe3+:Zn2+ Reactome DB_ID: 29426 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome DB_ID: 111736 1 iron(3+) [ChEBI:29034] iron(3+) Ferric ion ferric iron iron, ion (Fe(3+)) Fe3+ FE (III) ION Fe(III) Fe(3+) ChEBI 29034 Converted from EntitySet in Reactome Reactome DB_ID: 9808007 1 PPP3CA,B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ppp3ca [cytosol] Ppp3cb [cytosol] UniProt P63328 UniProt P48453 Reactome Database ID Release 78 9808009 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=9808009 Reactome R-MMU-2025949 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=R-MMU-2025949.1 Reactome DB_ID: 2025929 1 UniProt:Q63810 Ppp3r1 Ppp3r1 Ppp3r1 Cnb FUNCTION Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.SUBUNIT Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-binding subunit (also known as calcineurin B) (PubMed:26794871). There are three catalytic subunits, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two regulatory subunits which are also encoded by separate genes (PPP3R1 and PPP3R2). The regulatory subunit confers calcium sensitivity. Interacts with catalytic subunit PPP3CA/calcineurin A (PubMed:26794871). Interacts with catalytic subunit PPP3CB/calcineurin A (By similarity). Isoform 1 and isoform 2 interact with CIB1 (via C-terminal region); the interaction increases upon cardiomyocyte hypertrophy (PubMed:20639889).TISSUE SPECIFICITY Brain specific.MISCELLANEOUS This protein has four functional calcium-binding sites.SIMILARITY Belongs to the calcineurin regulatory subunit family. UniProt Q63810 2 EQUAL 170 EQUAL Reactome Database ID Release 78 9808011 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=9808011 Reactome R-MMU-2025977 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=R-MMU-2025977.1 Reactome DB_ID: 9808064 1 Calcineurin:Calmodulin (CaN:CaM) [cytosol] Calcineurin:Calmodulin (CaN:CaM) Reactome DB_ID: 2025906 1 Ppp3r1:Calcium [cytosol] Ppp3r1:Calcium Reactome DB_ID: 74016 4 Reactome DB_ID: 2025929 1 2 EQUAL 170 EQUAL Reactome Database ID Release 78 2025906 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=2025906 Reactome R-MMU-2025906 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=R-MMU-2025906.1 Reactome DB_ID: 9808062 1 PPP3CA,B:Calmodulin [cytosol] PPP3CA,B:Calmodulin Reactome DB_ID: 2025905 1 Reactome DB_ID: 9808009 1 Reactome Database ID Release 78 9808062 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=9808062 Reactome R-MMU-2026003 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=R-MMU-2026003.1 Reactome Database ID Release 78 9808064 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=9808064 Reactome R-MMU-2025947 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=R-MMU-2025947.1 Reactome Database ID Release 78 9814092 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=9814092 Reactome R-MMU-2730872 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=R-MMU-2730872.1 Calcineurin (CaN), also called protein phosphatase 2B (PP2B), is a calcium/Calmodulin (CaM)-dependent serine/threonine protein phosphatase. It exists as a heterodimer consisting of CaM-binding catalytic subunit CaN A chain and a Ca+2 binding regulatory CaN B chain. At low calcium concentrations, CaN exists in an inactive state, where the autoinhibitory domain (AID) binds to the active-site cleft. Upon an increase in calcium concentration CaM binds to Ca+2 ions and gets activated. Active CaM binds to CaN regulatory domain (RD) and this causes release of the AID and activation of the phosphatase (Rumi-Masante et al. 2012). Binding of calcium to CaN B regulatory chain also causes a conformational change of the RD of CaN A chain (Yang & Klee 2000). 18296442 Pubmed 2008 The secondary structure of calcineurin regulatory region and conformational change induced by calcium/calmodulin binding Shen, Xianrong Li, Huiming Ou, Yan Tao, Wenbing Dong, Aichun Kong, Jilie Ji, C Yu, Shaoning J. Biol. Chem. 283:11407-13 11015619 Pubmed 2000 Calcineurin: form and function Rusnak, F Mertz, P Physiol. Rev. 80:1483-521 22100452 Pubmed 2012 Structural basis for activation of calcineurin by calmodulin Rumi-Masante, Julie Rusinga, Farai I Lester, Terrence E Dunlap, Tori B Williams, Todd D Dunker, A Keith Weis, David D Creamer, Trevor P J. Mol. Biol. 415:307-17 11123943 Pubmed 2000 Low affinity Ca2+-binding sites of calcineurin B mediate conformational changes in calcineurin A Yang, S A Klee, C B Biochemistry 39:16147-54 inferred by electronic annotation IEA GO IEA Calcineurin binds and dephosphorylates NFAT Calcineurin binds and dephosphorylates NFAT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 9808060 1 p-NFATC1,2,3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Nfatc3 [cytosol] phospho-Nfatc2 [cytosol] phospho-Nfatc1 [cytosol] UniProt P97305 UniProt Q60591 UniProt O88942 Reactome DB_ID: 29356 1 Reactome DB_ID: 9808064 1 Reactome DB_ID: 29372 13 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 9813979 1 NFAT:CaN:CaM [cytosol] NFAT:CaN:CaM Converted from EntitySet in Reactome Reactome DB_ID: 9813977 1 Dephosphorylated NFAT [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Nfatc2 [cytosol] phospho-Nfatc1 [cytosol] phospho-Nfatc3 [cytosol] Reactome DB_ID: 9808064 1 Reactome Database ID Release 78 9813979 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=9813979 Reactome R-MMU-2685705 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=R-MMU-2685705.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9808064 GO 0033192 GO molecular function Reactome Database ID Release 78 9813980 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=9813980 Reactome Database ID Release 78 9813982 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=9813982 Reactome R-MMU-2730849 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=R-MMU-2730849.1 Nuclear factor of activated T-cells (NFAT) is a transcription factor which induces genes responsible for cytokine production, for cell-cell interactions etc. NFAT transcription activity is modulated by calcium and Calcineurin concentration. In resting cells NFAT is phosphorylated and resides in the cytoplasm. Phosphorylation sites are located in NFAT's regulatory domain in three different serine rich motifs, termed SRR1, SP2 and SP. Upon stimulation, these serine residues are dephosphorylated by calcineurin, that thought to cause exposure of nuclear localization signal sequences triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Among all the phosphorylation sites one of the site in SRR-2 motif is not susceptable to dephosphorylation by CaN (Takeuchi et al. 2007, Hogan et al. 2003). 8631904 Pubmed 1996 Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity Loh, C Shaw, KT Carew, J Viola, JP Luo, C Perrino, BA Rao, A J Biol Chem 271:10884-91 8799126 Pubmed 1996 Interaction of calcineurin with a domain of the transcription factor NFAT1 that controls nuclear import Luo, C Shaw, KT Raghavan, A Aramburu, J Garcia-Cozar, F Perrino, BA Hogan, PG Rao, A Proc Natl Acad Sci U S A 93:8907-12 10860980 Pubmed 2000 A second calcineurin binding site on the NFAT regulatory domain Park, S Uesugi, M Verdine, GL Proc Natl Acad Sci U S A 97:7130-5 11030334 Pubmed 2000 Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity Okamura, H Aramburu, J García-Rodríguez, C Viola, JP Raghavan, A Tahiliani, M Zhang, X Qin, J Hogan, PG Rao, A Mol Cell 6:539-50 12975316 Pubmed 2003 Transcriptional regulation by calcium, calcineurin, and NFAT Hogan, Patrick G Chen, L Nardone, J Rao, Anjana Genes Dev. 17:2205-32 17502104 Pubmed 2007 Structure of the calcineurin-NFAT complex: defining a T cell activation switch using solution NMR and crystal coordinates Takeuchi, Koh Roehrl, Michael H A Sun, Zhen-Yu J Wagner, Gerhard Structure 15:587-97 inferred by electronic annotation IEA GO IEA Translocation of CaN:CaM:NFAT to nucleus Translocation of CaN:CaM:NFAT to nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9813979 1 Reactome DB_ID: 9814078 1 NFAT:CaN:CaM [nucleoplasm] NFAT:CaN:CaM Reactome DB_ID: 9814068 1 CaN:CaM:Ca2+ [nucleoplasm] CaN:CaM:Ca2+ Reactome DB_ID: 9814066 1 CaN catalytic alpha/beta:Zn++:Fe3+:CaM:Ca2+ [nucleoplasm] CaN catalytic alpha/beta:Zn++:Fe3+:CaM:Ca2+ Reactome DB_ID: 9005860 1 Calmodulin:Calcium [nucleoplasm] Calmodulin:Calcium Reactome DB_ID: 29496 4 Reactome DB_ID: 9016933 1 2 EQUAL 149 EQUAL Reactome Database ID Release 78 9005860 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=9005860 Reactome R-MMU-9005860 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=R-MMU-9005860.1 Reactome DB_ID: 9814064 1 CaN catalytic alpha/beta:Zn++:Fe3+ [nucleoplasm] CaN catalytic alpha/beta:Zn++:Fe3+ Reactome DB_ID: 2685584 1 Converted from EntitySet in Reactome Reactome DB_ID: 9814062 1 CaN-catalytic alpha/beta chains [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Ppp3ca [nucleoplasm] Ppp3cb [nucleoplasm] Reactome DB_ID: 200493 1 Reactome Database ID Release 78 9814064 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=9814064 Reactome R-MMU-2685714 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=R-MMU-2685714.1 Reactome Database ID Release 78 9814066 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=9814066 Reactome R-MMU-2685716 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=R-MMU-2685716.1 Reactome DB_ID: 9814056 1 CaN alpha regulatory:Ca2+ [nucleoplasm] CaN alpha regulatory:Ca2+ Reactome DB_ID: 29496 4 Reactome DB_ID: 9814054 1 2 EQUAL 170 EQUAL Reactome Database ID Release 78 9814056 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=9814056 Reactome R-MMU-2685704 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=R-MMU-2685704.1 Reactome Database ID Release 78 9814068 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=9814068 Reactome R-MMU-2685698 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=R-MMU-2685698.1 Converted from EntitySet in Reactome Reactome DB_ID: 9814076 1 Dephosphorylated NFATC1,2,3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Nfatc2 [nucleoplasm] phospho-Nfatc1 [nucleoplasm] phospho-Nfatc3 [nucleoplasm] Reactome Database ID Release 78 9814078 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=9814078 Reactome R-MMU-2685690 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=R-MMU-2685690.1 Reactome Database ID Release 78 9814080 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=9814080 Reactome R-MMU-2730867 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=R-MMU-2730867.1 Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g..IL2). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 9862438 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=9862438 Reactome R-MMU-2871809 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=R-MMU-2871809.1 Increase of intracellular calcium in mast cells is most crucial for mast cell degranulation. Elevation of intracellular calcium is achieved by activation of PLC-gamma. Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms and activation of these enzymes leads to conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). The production of IP3 leads to mobilization of intracellular Ca+2, which later results in a sustained Ca+2 flux response that is maintained by an influx of extracellular Ca+2. In addition to degranulation, an increase in intracellular calcium concentration also activates the Ca2+/calmodulin-dependent serine phosphatase calcineurin. Calcineurin dephosphorylates the nuclear factor for T cell activation (NFAT) which exposes nuclear-localization signal sequence triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Once in the nucleus, NFAT regulates the transcription of several cytokine genes (Kambayashi et al. 2007, Hoth & Penner 1992, Ebinu et al. 2000, Siraganian et al). 17336609 Pubmed 2007 Proximal signaling events in Fc epsilon RI-mediated mast cell activation Kambayashi, Taku Koretzky, Gary A J. Allergy Clin. Immunol. 119:544-52; quiz 553-4 10807788 Pubmed 2000 RasGRP links T-cell receptor signaling to Ras Ebinu, J O Stang, S L Teixeira, C Bottorff, D A Hooton, J Blumberg, P M Barry, M Bleakley, R C Ostergaard, H L Stone, J C Blood 95:3199-203 1309940 Pubmed 1992 Depletion of intracellular calcium stores activates a calcium current in mast cells Hoth, M Penner, R Nature 355:353-6 inferred by electronic annotation IEA GO IEA FCERI mediated NF-kB activation FCERI mediated NF-kB activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Translocation of PKC theta to plasma membrane Translocation of PKC theta to plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9770637 1 UniProt:Q02111 Prkcq UniProt Q02111 1 EQUAL 706 EQUAL Reactome DB_ID: 112275 1 Reactome DB_ID: 9771293 1 PKC-theta (open): DAG [plasma membrane] PKC-theta (open): DAG Reactome DB_ID: 9771291 1 1 EQUAL 706 EQUAL Reactome DB_ID: 112275 1 Reactome Database ID Release 78 9771293 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=9771293 Reactome R-MMU-202187 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=R-MMU-202187.1 Reactome Database ID Release 78 9771299 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=9771299 Reactome R-MMU-202328 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=R-MMU-202328.1 DAG along with intracellular calcium signals cooperatively to activate PKCs, which then trigger other pathways such as the NF-kB pathway, ultimately leading to mast cell (MC) degranulation and cytokine production (Wu 2011). PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates.<br>MCs express several Protein kinase C (PKC) isozymes and these kinases are involved in both the activation and termination of the degranulation process. PKC-delta is a negative regulator of FCERI mediated mast cell degranulation, whereas PKC-theta facilitates in degranulation (Leitges et al. 2002, Liu et al. 2001). In response to FCERI activation PKC-theta translocates to membrane by binding to DAG with its C1 domain. PKC-theta exists in two conformations closed/inactive and open/active state. In resting state, PKC-theta is autoinhibited where the pseudosubstrate sequence in the N-terminal regulatory region of PKC-theta forms intramolecular interaction with the substrate-binding region in the catalytic domain. This prevents the catalytic domain gaining access to substrates. The allosteric change of PKC-theta from closed to open state involves two important mechanisms: DAG binding to the C1 domains and autophosphorylation of T538 on the activation loop. Interaction with DAG induces conformational change resulting in the exposure of the activation loop of PKC-theta (Wang et al. 2012, Melowic et al. 2007). 11358993 Pubmed 2001 Protein kinase C theta is expressed in mast cells and is functionally involved in Fcepsilon receptor I signaling Liu, Y Graham, C Parravicini, V Brown, M J Rivera, J Shaw, S J. Leukoc. Biol. 69:831-40 12473184 Pubmed 2002 Protein kinase C-theta (PKC theta): a key enzyme in T cell life and death Altman, A Villalba, M J Biochem (Tokyo) 132:841-6 17548359 Pubmed 2007 Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Ctheta Melowic, Heather R Stahelin, Robert V Blatner, Nichole R Tian, Wen Hayashi, Keitaro Altman, Amnon Cho, Wonhwa J. Biol. Chem. 282:21467-76 16978534 Pubmed 2006 Selective function of PKC-theta in T cells Manicassamy, S Gupta, S Sun, Z Cell Mol Immunol 3:263-70 inferred by electronic annotation IEA GO IEA 2.7.10 Phosphorylation of PKC-theta Phosphorylation of PKC-theta This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9771293 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 Reactome DB_ID: 9771227 1 p-Y90-PKC-theta:DAG [plasma membrane] p-Y90-PKC-theta:DAG Reactome DB_ID: 9771225 1 O4'-phospho-L-tyrosine at 90 (in Homo sapiens) 90 EQUAL 1 EQUAL 706 EQUAL Reactome DB_ID: 112275 1 Reactome Database ID Release 78 9771227 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=9771227 Reactome R-MMU-202300 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=R-MMU-202300.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9812815 Reactome Database ID Release 78 9814096 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=9814096 Reactome Database ID Release 78 9814098 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=9814098 Reactome R-MMU-2730882 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=R-MMU-2730882.1 Raft localized PKC-theta is phosphorylated and is activated. Phosphorylation of both tyrosine and serine-threonine residues is important in the regulation of PKC function. Six phosphorylation sites have been identified on PKC-theta: Y90, T219, T538, S676, S685, and S695. Phosphorylation of Y90 positively regulates NF-AT and NF-kB activation in T-cells. In mast cells Src family members Src and LYN have been shown to be involved in phosphorylating Y90 (Wang et al. 2012, Liu et al. 2001). inferred by electronic annotation IEA GO IEA Autophosphorylation of PKC-theta Autophosphorylation of PKC-theta This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 4 Reactome DB_ID: 9771227 1 Reactome DB_ID: 29370 4 Reactome DB_ID: 9813918 1 p-5Y-PKC-theta:DAG [plasma membrane] p-5Y-PKC-theta:DAG Reactome DB_ID: 112275 1 Reactome DB_ID: 9813916 1 O4'-phospho-L-tyrosine at 90 (in Homo sapiens) 90 EQUAL O-phospho-L-threonine at 219 (in Homo sapiens) 219 EQUAL O-phospho-L-threonine at 538 (in Homo sapiens) 538 EQUAL O-phospho-L-serine at 676 (in Homo sapiens) 676 EQUAL O-phospho-L-serine at 695 (in Homo sapiens) 695 EQUAL 1 EQUAL 706 EQUAL Reactome Database ID Release 78 9813918 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=9813918 Reactome R-MMU-2685674 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=R-MMU-2685674.1 Reactome Database ID Release 78 9813920 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=9813920 Reactome R-MMU-2730835 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=R-MMU-2730835.1 T219, T538 at the activation loop, S676 at the turn motif and S695 at the hydrophobic motif are autophosphorylated in cis-maanner. Posphorylation of T538 is critical for kinase activation and it stabilises the open active conformation. Some studies suggest the involvement of PDK1 (3-phosphoinositide-dependent protein kinase 1) and GLK kinases in the phosphorylation T538. 16252004 Pubmed 2005 Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes Thuille, Nikolaus Heit, Isabelle Fresser, Friedrich Krumböck, Nina Bauer, Birgit Leuthaeusser, Sabine Dammeier, Sascha Graham, Caroline Copeland, Terry D Shaw, Steve Baier, Gottfried EMBO J. 24:3869-80 11772397 Pubmed 2002 Phosphorylation of the protein kinase C-theta activation loop and hydrophobic motif regulates its kinase activity, but only activation loop phosphorylation is critical to in vivo nuclear-factor-kappaB induction Liu, Yin Graham, Caroline Li, Aiqun Fisher, Robert J Shaw, Stephen Biochem. J. 361:255-65 22798961 Pubmed 2012 Regulation of PKC-? function by phosphorylation in T cell receptor signaling Wang, Xiaohong Chuang, Huai-Chia Li, Ju-Pi Tan, Tse-Hua Front Immunol 3:197 inferred by electronic annotation IEA GO IEA 2.7.11.13 Phosphorylation of CARMA1 by PKC-theta Phosphorylation of CARMA1 by PKC-theta This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9814033 1 UniProt:Q8CIS0 Card11 Card11 Card11 Carma1 FUNCTION Adapter protein that plays a key role in adaptive immune response by transducing the activation of NF-kappa-B downstream of T-cell receptor (TCR) and B-cell receptor (BCR) engagement (PubMed:12356734, PubMed:12154356, PubMed:16356855). Transduces signals downstream TCR or BCR activation via the formation of a multiprotein complex together with BCL10 and MALT1 that induces NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:12356734, PubMed:12154356, PubMed:16356855). Upon activation in response to TCR or BCR triggering, CARD11 homooligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10 and subsequent recruitment of MALT1: this leads to I-kappa-B kinase (IKK) phosphorylation and degradation, and release of NF-kappa-B proteins for nuclear translocation (By similarity). Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (By similarity). Promotes linear ubiquitination of BCL10 by promoting the targeting of BCL10 to RNF31/HOIP (By similarity). Stimulates the phosphorylation of BCL10 (By similarity). Also activates the TORC1 signaling pathway (By similarity).ACTIVITY REGULATION Maintained in an autoinhibited state via homodimerization in which the CARD domain forms an extensive interaction with the adjacent linker and coiled-coil regions (By similarity). Activation downstream of T-cell receptor (TCR) by phosphorylation by PRKCB and PRKCQ triggers CARD11 homooligomerization and BCL10 recruitment, followed by activation of NF-kappa-B (PubMed:16356855).SUBUNIT Homodimer; disulfide-linked (By similarity). Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (By similarity). Interacts (via CARD domain) with BCL10 (via CARD domain); interaction takes place following CARD11 activation and polymerization, leading to the formation of a filamentous CBM complex assembly (PubMed:22880103). Component of a CBM complex (CARD11-BCL10-MALT1) complex involved in NF-kappa-B activation (By similarity). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (By similarity). Interacts (via PDZ domain) with DPP4 (via cytoplasmic tail) (By similarity).DOMAIN The linker region, also named autoinhibitory interface, is less inhibitory on its own than that of CARD9. The linker region together with the inhibitory domain (ID) are required to prevent constitutive activation and maintain CARD11 in an autoinhibitory state. Disruption of the inhibitory domain (ID) region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments.PTM Phosphorylation at Ser-564, Ser-649 and Ser-657 by PRKCB and PRKCQ leads to a shift from an inactive to an active form that activates the NF-kappa-B signaling.DISRUPTION PHENOTYPE Impaired activation of NF-kappa-B downstream of T-cell receptor (TCR), leading to defects in interleukin-2 (IL2) production. UniProt Q8CIS0 1 EQUAL 1154 EQUAL Reactome DB_ID: 9813918 1 Reactome DB_ID: 29370 2 Reactome DB_ID: 9814035 1 DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 [plasma membrane] DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 Reactome DB_ID: 9813918 1 Reactome DB_ID: 9814016 1 O-phospho-L-serine at 552 (in Homo sapiens) 552 EQUAL O-phospho-L-serine at 645 (in Homo sapiens) 645 EQUAL 1 EQUAL 1154 EQUAL Reactome Database ID Release 78 9814035 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=9814035 Reactome R-MMU-2685711 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=R-MMU-2685711.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9813918 GO 0004697 GO molecular function Reactome Database ID Release 78 9814036 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=9814036 Reactome Database ID Release 78 9814038 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=9814038 Reactome R-MMU-2730863 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=R-MMU-2730863.1 CARMA1 (CARD11/Caspase recruitment domain-containing protein 11), BCL10 (B-cell lymphoma/leukemia 10) and MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1)/paracaspase have been identified as signaling components that act downstream of PKC-theta. CARMA1 is a scaffold protein and recruits BCL10, MALT1, PKC and TRAF6 to form a multi protein complex. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. Upon stimulation S552 and S645 linker residues are phosphorylated by PKC-theta and this may weaken this interaction, inducing an open conformation of CARMA1. Further phosphorylation studies have revealed other phosphorylation sites (S109, S551 and S555) that may also promote activation of CARMA1. Serene/threonine kinases PKC-beta, IKKbeta, HPK1 and CaMKII are involved in triggering CARMA1 activation (Thome et al. 2010, Rueda & Thome 2005). (only phosphorylated S552 and S645 are represented in this reaction) 16356856 Pubmed 2005 Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation Matsumoto, Reiko Wang, Donghai Blonska, Marzenna Li, Hongxiu Kobayashi, Masayuki Pappu, Bhanu Chen, Yuhong Wang, Demin Lin, Xin Immunity 23:575-85 16356853 Pubmed 2005 Phosphorylation of CARMA1: the link(er) to NF-kappaB activation Rueda, D Thome, M Immunity 23:551-3 20685844 Pubmed 2010 Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1 Thome, Margot Charton, Jean Enno Pelzer, Christiane Hailfinger, Stephan Cold Spring Harb Perspect Biol 2:a003004 inferred by electronic annotation IEA GO IEA Oligomerization of p-CARMA1 Oligomerization of p-CARMA1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9814035 1 Reactome DB_ID: 9814016 1 O-phospho-L-serine at 552 (in Homo sapiens) 552 EQUAL O-phospho-L-serine at 645 (in Homo sapiens) 645 EQUAL 1 EQUAL 1154 EQUAL Reactome DB_ID: 9814127 1 DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomer [plasma membrane] DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomer Reactome DB_ID: 9813918 1 Reactome DB_ID: 9814018 1 p-CARMA1 oligomer [plasma membrane] p-CARMA1 oligomer Reactome Database ID Release 78 9814127 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=9814127 Reactome R-MMU-2685699 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=R-MMU-2685699.1 Reactome Database ID Release 78 9814129 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=9814129 Reactome R-MMU-2730902 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=R-MMU-2730902.1 CARMA1 phosphorylation initiates its oligomerization and the coiled-coil (CC) domain of CARMA1 is hypothesized to mediate this clustering (Tanner et al. 2007). 17428801 Pubmed 2007 CARMA1 coiled-coil domain is involved in the oligomerization and subcellular localization of CARMA1 and is required for T cell receptor-induced NF-kappaB activation Tanner, MJ Hanel, W Gaffen, SL Lin, X J Biol Chem 282:17141-7 inferred by electronic annotation IEA GO IEA Oligomerization of BCL10 and MALT1 Oligomerization of BCL10 and MALT1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9814120 1 DAG:p-5Y-PKC-theta:CBM complex [plasma membrane] DAG:p-5Y-PKC-theta:CBM complex Reactome DB_ID: 9814118 1 p-CARMA1 oligomer:BCL10:MALT1 (CBM complex) [plasma membrane] p-CARMA1 oligomer:BCL10:MALT1 (CBM complex) Reactome DB_ID: 9814018 1 Reactome DB_ID: 9814116 1 BCL10:MALT1 [cytosol] BCL10:MALT1 Reactome DB_ID: 2685587 1 UniProt:Q9Z0H7 Bcl10 Bcl10 Ciper Clap Bcl10 FUNCTION Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation (PubMed:22265677). Acts by channeling adaptive and innate immune signaling downstream of CARD domain-containing proteins CARD9, CARD11 and CARD14 to activate NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:22265677). Recruited by activated CARD domain-containing proteins: homooligomerized CARD domain-containing proteins form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10, subsequent recruitment of MALT1 and formation of a CBM complex (By similarity). This leads to activation of NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (By similarity). Activated by CARD9 downstream of C-type lectin receptors; CARD9-mediated signals are essential for antifungal immunity (PubMed:22265677). Activated by CARD11 downstream of T-cell receptor (TCR) and B-cell receptor (BCR) (By similarity). Promotes apoptosis, pro-caspase-9 maturation and activation of NF-kappa-B via NIK and IKK (By similarity).SUBUNIT Homomultimer; homooligomerized following recruitment by CARD domain-containing proteins that form a nucleating helical template that recruits BCL10 via CARD-CARD interaction (By similarity). Self-associates by CARD-CARD interaction and interacts with other CARD-proteins such as CARD9, CARD10, CARD11 and CARD14 (PubMed:22265677, PubMed:22880103). Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex (By similarity). Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (By similarity). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (PubMed:22265677). Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (By similarity). Binds caspase-9 with its C-terminal domain (By similarity). Interacts with TRAF2 and BIRC2/c-IAP2 (By similarity). Interacts with PELI2 and SOCS3; these interactions may be mutually exclusive (PubMed:15213237).TISSUE SPECIFICITY Highly expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Detected in developing brain, olfactory epithelium, tongue, whisker follicles, salivary gland, heart, lung, liver and intestinal epithelia of stage 15 embryos.PTM Phosphorylated by IKBKB/IKKB.PTM Ubiquitinated via both 'Lys-63'-linked and linear ('Met-1'-linked) polyubiquitin chains in response to T-cell receptor (TCR) activation. Ubiquitination is recognized by IKBKG/NEMO, the regulatory subunit of I-kappa-B kinase (IKK), and is required for TCR-induced NF-kappa-B activation. Linear ubiquitination at Lys-17, Lys-31 and Lys-63 is mediated by RNF31/HOIP; linear ubiquitination is recognized with much higher affinity than 'Lys-63'-linked ubiquitin by IKBKG/NEMO. CARD11 is required for linear ubiquitination by HOIP by promoting the targeting of BCL10 to RNF31/HOIP.PTM Proteolytically cleaved by MALT1; required for T-cell activation. UniProt Q9Z0H7 1 EQUAL 233 EQUAL Reactome DB_ID: 9771352 1 UniProt:Q2TBA3 Malt1 Malt1 Malt1 FUNCTION Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP kinase p38 pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (By similarity). Mediates BCL10 cleavage: MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion (By similarity). Involved in the induction of T helper 17 cells (Th17) differentiation (By similarity). Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (PubMed:25282160). Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation. May also have ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity (By similarity).SUBUNIT Homooligomer; forms oligomers which bind to TRAF6. Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex. Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (By similarity). Forms a complex with CARD9 and MALT1; resulting in the formation of a CBM (CARD9-BCL10-MALT1) complex (PubMed:22265677).SIMILARITY Belongs to the peptidase C14B family. UniProt Q2TBA3 1 EQUAL 824 EQUAL Reactome Database ID Release 78 9814116 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=9814116 Reactome R-MMU-2685715 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=R-MMU-2685715.1 Reactome Database ID Release 78 9814118 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=9814118 Reactome R-MMU-2685679 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=R-MMU-2685679.1 Reactome DB_ID: 9813918 1 Reactome Database ID Release 78 9814120 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=9814120 Reactome R-MMU-2685688 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=R-MMU-2685688.1 Reactome DB_ID: 2685587 1 1 EQUAL 233 EQUAL Reactome DB_ID: 9771352 1 1 EQUAL 824 EQUAL Reactome DB_ID: 9814042 1 DAG:p-5Y-PKC-theta:CBM oligomer [plasma membrane] DAG:p-5Y-PKC-theta:CBM oligomer Reactome DB_ID: 9813918 1 Reactome DB_ID: 9814040 1 CBM oligomer [plasma membrane] CBM oligomer Reactome DB_ID: 9814011 1 BCL10 oligomer [cytosol] BCL10 oligomer Reactome DB_ID: 9814013 1 MALT1 oligomer [cytosol] MALT1 oligomer Reactome DB_ID: 9814018 1 Reactome Database ID Release 78 9814040 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=9814040 Reactome R-MMU-2685684 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=R-MMU-2685684.1 Reactome Database ID Release 78 9814042 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=9814042 Reactome R-MMU-2685671 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=R-MMU-2685671.1 Reactome Database ID Release 78 9814122 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=9814122 Reactome R-MMU-2730899 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=R-MMU-2730899.1 BCL10 and MALT1 proteins form high molecular weight oligomers and only these oligomeric forms can activate IKK in vitro (Sun et al. 2004). BCL10 proteins form homo-oligomers through CARD-CARD interactions whereas in MALT1 the tandem Ig-like domains naturally form oligomers with a tendency towards dimers and tetramers (Dong et al. 2006, Quiu & Dhe-Paganon 2011). These CBM oligomers provides the molecular platform, which can facilitate dimerization or serve as scaffolds on which proteases and kinases involved in NF-kB activation are assembled and activated. 16831874 Pubmed 2006 The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4 Dong, W Liu, Y Peng, J Chen, L Zou, T Xiao, H Liu, Z Li, W Bu, Y Qi, Y J Biol Chem 281:26029-40 21966355 Pubmed 2011 Oligomeric structure of the MALT1 tandem Ig-like domains Qiu, Liyan Dhe-Paganon, Sirano PLoS ONE 6:e23220 inferred by electronic annotation IEA GO IEA Recruitment of TRAF6 to CBM complex by binding to MALT1 Recruitment of TRAF6 to CBM complex by binding to MALT1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9814042 1 Reactome DB_ID: 9763826 1 UniProt:P70196-1 Traf6 Traf6 Traf6 FUNCTION E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (By similarity). Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homotrimer (By similarity). Homooligomer (By similarity). N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK (By similarity). Associates with NGFR, TNFRSF17, IRAK2, IRAK3, PELI2, PELI3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1 (By similarity). Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. Interacts with IL1RL1. Interacts with AJUBA (By similarity). Interacts with TRAFD1. Interacts with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2 (By similarity). Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal) (By similarity). Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with RBCK1 (By similarity). Interacts with LIMD1 (via LIM domains). Interacts with RSAD2/viperin. Interacts with IFIT3 (via N-terminus) (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain). Interacts with CARD14 (By similarity). Interacts with CD40 and MAP3K8; the interaction is required for ERK activation. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity). Interacts with TANK; this interaction increases in response to DNA damage (By similarity). Interacts with USP10; this interaction increases in response to DNA damage (By similarity). Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (By similarity). Interacts with WDFY3 (PubMed:27330028). Interacts with TRIM13 (By similarity). Interacts with GPS2 (PubMed:22424771). Interacts (via C-terminus) with SASH1 (By similarity). Interacts with LRRC19 (By similarity). Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70 (By similarity).TISSUE SPECIFICITY Highly expressed in brain, lung, liver, skeletal muscle, and kidney; lower expression in heart, spleen, and testis.DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.PTM Sumoylated on Lys-124, Lys-142 and Lys-461 with SUMO1.PTM Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (By similarity). Polyubiquitinated; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).DISRUPTION PHENOTYPE Abrogation of IL-1-induced activation of NF-kappa-B, MAPK8/JNK and MAPK14/p38. Animals appear normal at birth but become smaller after one week. Show runting, failure of tooth eruption and die after three weeks. Exhibit severe osteopetrosis, thymic atrophy, lymph node deficiency, splenomegaly, and have alopecia and lack sweat glands.SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily. UniProt P70196-1 1 EQUAL 522 EQUAL Reactome DB_ID: 9814050 1 DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 [plasma membrane] DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 Reactome DB_ID: 9813918 1 Reactome DB_ID: 9814048 1 CBM oligomer:TRAF6 [plasma membrane] CBM oligomer:TRAF6 Reactome DB_ID: 9814018 1 Reactome DB_ID: 9814046 1 BCL10 oligomer:MALT1 oligomer:TRAF6 [cytosol] BCL10 oligomer:MALT1 oligomer:TRAF6 Reactome DB_ID: 9814011 1 Reactome DB_ID: 9814044 1 MALT1oligomer:TRAF6 [cytosol] MALT1oligomer:TRAF6 Reactome DB_ID: 9814013 1 Reactome DB_ID: 9763826 1 1 EQUAL 522 EQUAL Reactome Database ID Release 78 9814044 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=9814044 Reactome R-MMU-2685676 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=R-MMU-2685676.1 Reactome Database ID Release 78 9814046 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=9814046 Reactome R-MMU-2685667 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=R-MMU-2685667.1 Reactome Database ID Release 78 9814048 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=9814048 Reactome R-MMU-2685697 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=R-MMU-2685697.1 Reactome Database ID Release 78 9814050 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=9814050 Reactome R-MMU-2685682 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=R-MMU-2685682.1 Reactome Database ID Release 78 9814052 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=9814052 Reactome R-MMU-2730864 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=R-MMU-2730864.1 TRAF6 is a ubiquitin ligase that plays a central role in the IKK-dependent canonical NF-kB pathway. It is recruited to the CBM complex by binding to MALT1. The MALT1 C-terminal Ig domain and extension contain two binding motifs for TRAF6 (Noels et al 2007). After oligomerzation TRAF6, together with Ubc13/Uev1A, activates TAK1 and IKK. It also acts as an E3 ligase for MALT1 and mediates lysine 63-linked ubiquitination (Oeckinghaus et al. 2007). 17287209 Pubmed 2007 A Novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-kappaB activation by API2middle dotMALT1 fusions Noels, Heidi van Loo, G Hagens, Sofie Broeckx, Vicky Beyaert, Rudi Marynen, P Baens, Mathijs J. Biol. Chem. 282:10180-9 18772140 Pubmed 2008 TRAF6 specifically contributes to FcepsilonRI-mediated cytokine production but not mast cell degranulation Yang, Yong Jun Chen, Wei Carrigan, Svetlana O Chen, Wei-Min Roth, Kristy Akiyama, Taishin Inoue, Jun-ichiro Marshall, Jean S Berman, Jason N Lin, Tong-Jun J. Biol. Chem. 283:32110-8 17948050 Pubmed 2007 Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation Oeckinghaus, Andrea Wegener, Elmar Welteke, Verena Ferch, Uta Arslan, Seda Cöl Ruland, Jürgen Scheidereit, Claus Krappmann, Daniel EMBO J. 26:4634-45 inferred by electronic annotation IEA GO IEA Oligomerization of TRAF6 Oligomerization of TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9814050 1 Reactome DB_ID: 9763826 1 1 EQUAL 522 EQUAL Reactome DB_ID: 9814135 1 DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomer [plasma membrane] DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomer Reactome DB_ID: 9814133 1 CBM oligomer:TRAF6 oligomer [plasma membrane] CBM oligomer:TRAF6 oligomer Reactome DB_ID: 9814011 1 Reactome DB_ID: 9814013 1 Reactome DB_ID: 9814018 1 Reactome DB_ID: 9814131 1 TRAF6 oligomer [cytosol] TRAF6 oligomer Reactome Database ID Release 78 9814133 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=9814133 Reactome R-MMU-2685695 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=R-MMU-2685695.1 Reactome DB_ID: 9813918 1 Reactome Database ID Release 78 9814135 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=9814135 Reactome R-MMU-2685713 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=R-MMU-2685713.1 Reactome Database ID Release 78 9814137 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=9814137 Reactome R-MMU-2730903 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=R-MMU-2730903.1 BCL10-MALT1 oligomers bind to TRAF6 and this in turn promotes the oligomerization of TRAF6 and activates its E3 ligase activity (Sun et al. 2004). 15125833 Pubmed 2004 The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes Sun, L Deng, L Ea, CK Xia, ZP Chen, ZJ Mol Cell 14:289-301 inferred by electronic annotation IEA GO IEA 6.3.2.19 Auto-ubiquitination of TRAF6 Auto-ubiquitination of TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764075 1 UBE2N:UBE2V1 [cytosol] UBE2N:UBE2V1 Reactome DB_ID: 9764069 1 UniProt:P61089 Ube2n UniProt P61089 1 EQUAL 152 EQUAL Reactome DB_ID: 9764073 1 UniProt:Q9CZY3 Ube2v1 UniProt Q9CZY3 2 EQUAL 147 EQUAL Reactome Database ID Release 78 9764075 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=9764075 Reactome R-MMU-202463 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=R-MMU-202463.1 Reactome DB_ID: 113592 1 Reactome DB_ID: 9764139 1 K63polyUb [cytosol] K63polyUb Reactome DB_ID: 9814135 1 Reactome DB_ID: 9764075 1 Reactome DB_ID: 111294 1 diphosphate(3-) [ChEBI:33019] diphosphate(3-) ChEBI 33019 Reactome DB_ID: 9814022 1 DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6 [plasma membrane] DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6 Reactome DB_ID: 9813918 1 Reactome DB_ID: 9814020 1 CBM oligomer:oligo-K63-poly Ub-TRAF6 oligomer [plasma membrane] CBM oligomer:oligo-K63-poly Ub-TRAF6 oligomer Reactome DB_ID: 9814011 1 Reactome DB_ID: 9814013 1 Reactome DB_ID: 9814018 1 Reactome DB_ID: 9764065 1 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 124 (in Homo sapiens) 124 EQUAL ubiquitinylated lysine [MOD:01148] 1 EQUAL 522 EQUAL Reactome Database ID Release 78 9814020 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=9814020 Reactome R-MMU-2685678 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=R-MMU-2685678.1 Reactome Database ID Release 78 9814022 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=9814022 Reactome R-MMU-2685691 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=R-MMU-2685691.1 Reactome DB_ID: 76577 1 adenosine 5'-monophosphate(2-) [ChEBI:456215] adenosine 5'-monophosphate(2-) Adenosine-5-monophosphate(2-) AMP 5'-O-phosphonatoadenosine AMP dianion AMP(2-) Adenosine-5-monophosphate dianion ChEBI 456215 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9814135 GO 0004842 GO molecular function Reactome Database ID Release 78 9814138 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=9814138 Reactome Database ID Release 78 9814140 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=9814140 Reactome R-MMU-2730904 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=R-MMU-2730904.1 TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex. 17135271 Pubmed 2007 Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation Lamothe, B Besse, A Campos, AD Webster, WK Wu, H Darnay, BG J Biol Chem 282:4102-12 inferred by electronic annotation IEA GO IEA Recruitment of TAK1 kinase complex to oligo-K63-pUb-TRAF6 Recruitment of TAK1 kinase complex to oligo-K63-pUb-TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9814022 1 Reactome DB_ID: 9764094 1 TAK1 complex [cytosol] TAK1 complex Converted from EntitySet in Reactome Reactome DB_ID: 9764092 1 TAB2,TAB3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Tab2 [cytosol] Tab3 [cytosol] UniProt Q99K90 UniProt Q571K4 Reactome DB_ID: 9764080 1 UniProt:Q62073 Map3k7 Map3k7 Tak1 Map3k7 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR) (PubMed:10748100, PubMed:16157589, PubMed:21183079, PubMed:29291351). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK (PubMed:16157589, PubMed:8533096, PubMed:29291351). MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis (PubMed:10748100). In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity (By similarity). Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (PubMed:28842570).ACTIVITY REGULATION Activated by proinflammatory cytokines and in response to physical and chemical stresses, including osmotic stress, oxidative stress, arsenic and ultraviolet light irradiation. Activated by 'Lys-63'-linked polyubiquitination and by autophosphorylation. Association with TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 promotes activation through autophosphorylation, whereas PPM1B/PP2CB, PP2A and PPP6C dephosphorylation leads to inactivation.SUBUNIT Can form homodimer (By similarity). Binds both upstream activators and downstream substrates in multimolecular complexes (By similarity). Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3 (By similarity). Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2 (By similarity). Interacts with PPM1L and PPM1B/PP2CB (PubMed:12556533). Interaction with PP2A and PPP6C leads to its repressed activity (By similarity). Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling (By similarity). Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation (By similarity). Interacts with DYNC2I2 (via WD domains) (By similarity). Interacts with CYLD and RBCK1 (PubMed:17548520). Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6 (By similarity). Interacts with MAPK8IP1 and SMAD6 (PubMed:10748100, PubMed:17709393). Interacts with isoform 1 of VRK2 (PubMed:17709393). Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation (By similarity). Interacts with TRIM5 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with PLEKHM1 (via N- and C-terminus) (PubMed:27777970). Interacts with TRIM8 (By similarity). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2 (PubMed:27084103). Interacts with SASH1 (By similarity). Interacts with RIPK1 (PubMed:31519887).PTM Association with TAB1/MAP3K7IP1 promotes autophosphorylation and subsequent activation. Association with TAB2/MAP3K7IP2, itself associated with free unanchored Lys-63 polyubiquitin chain, promotes autophosphorylation and subsequent activation of MAP3K7. Dephosphorylation at Thr-187 by PP2A and PPP6C leads to inactivation (By similarity).PTM 'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation (PubMed:16157589). Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH (PubMed:25632008). 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains (PubMed:17548520, PubMed:29291351).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. UniProt Q62073 1 EQUAL 606 EQUAL Reactome DB_ID: 9764083 1 UniProt:Q8CF89 Tab1 Tab1 Map3k7ip1 Tab1 FUNCTION May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.SUBUNIT Interacts with XIAP and BIRC7. Interacts with TRAF6 and MAP3K7; during IL-1 signaling. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2 (By similarity).PTM Monoubiquitinated.CAUTION Lacks several key residues involved in metal-binding and catalytic activity, therefore has lost phosphatase activity. UniProt Q8CF89 1 EQUAL 504 EQUAL Reactome Database ID Release 78 9764094 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=9764094 Reactome R-MMU-446878 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=R-MMU-446878.1 Reactome DB_ID: 9814024 1 DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3 [plasma membrane] DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3 Reactome DB_ID: 9814022 1 Reactome DB_ID: 9764094 1 Reactome Database ID Release 78 9814024 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=9814024 Reactome R-MMU-2685689 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=R-MMU-2685689.1 Reactome Database ID Release 78 9814026 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=9814026 Reactome R-MMU-2730861 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=R-MMU-2730861.1 K-63 linked polyubiquitin (pUb) chain on TRAF6 provides a scaffold to recruit downstream effector molecules to activate NF-kB. Transforming growth factor beta-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family is shown to be an essential intermediate that transmits the upstream signals from the receptor complex to the downstream MAPKs and to the NF-kB pathway (Broglie et al. 2009). TAK1-binding protein 1 (TAB1), TAB2 and TAB3 constitutively bound to TAK1. TAB1 acts as the activation subunit of the TAK1 complex, aiding in the autophosphorylation of TAK1, whereas TAB2 and its homologue TAB3, act as a adaptors of TAK1 that facilitate the assembly of TAK1 complex to TRAF6. The highly conserved C-terminal zinc finger domain of TAB2 and TAB3 binds preferentially to the K-63-linked polyubiquitin chains on TRAF6 (Broglie et al. 2009, Besse et al. 2007). 19955178 Pubmed 2010 Transforming growth factor beta-activated kinase 1 (TAK1) kinase adaptor, TAK1-binding protein 2, plays dual roles in TAK1 signaling by recruiting both an activator and an inhibitor of TAK1 kinase in tumor necrosis factor signaling pathway Broglie, Peter Matsumoto, Kunihiro Akira, Shizuo Brautigan, David L Ninomiya-Tsuji, Jun J. Biol. Chem. 285:2333-9 15327770 Pubmed 2004 TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains Kanayama, A Seth, RB Sun, L Ea, CK Hong, M Shaito, A Chiu, YH Deng, L Chen, ZJ Mol Cell 15:535-48 17158449 Pubmed 2007 TAK1-dependent signaling requires functional interaction with TAB2/TAB3 Besse, A Lamothe, B Campos, AD Webster, WK Maddineni, U Lin, SC Wu, H Darnay, BG J Biol Chem 282:3918-28 10882101 Pubmed 2000 TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway Takaesu, G Kishida, S Hiyama, A Yamaguchi, K Shibuya, H Irie, K Ninomiya-Tsuji, J Matsumoto, K Mol Cell 5:649-58 inferred by electronic annotation IEA GO IEA 2.7.11 Activation of TAK1 complex bound to pUb-TRAF6 Activation of TAK1 complex bound to pUb-TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113592 2 Reactome DB_ID: 9814024 1 Reactome DB_ID: 29370 2 Reactome DB_ID: 9814024 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9814024 Reactome Database ID Release 78 9814123 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=9814123 Reactome Database ID Release 78 9814125 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=9814125 Reactome R-MMU-2730900 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=R-MMU-2730900.1 Binding of TAB2 and TAB3 to K63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Phosphorylation of TAK1 within the activation loop of the kinase is absolutely required for TAK1 activity. TAB1 is known to augment TAK1 catalytic activity by mediating spontaneous oligomerization and induces autophosphorylation of TAK1 (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Some biochemical studies revealed that free K63 polyubiquitin chains, which are not conjugated to any cellular protein, can directly activate the TAK1 kinase complex (Xia et al. 2009). 10838074 Pubmed 2000 Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1 Sakurai, H Miyoshi, H Mizukami, J Sugita, T FEBS Lett. 474:141-5 10702308 Pubmed 2000 TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop Kishimoto, K Matsumoto, K Ninomiya-Tsuji, J J Biol Chem 275:7359-64 17496917 Pubmed 2007 Ubiquitin-mediated activation of TAK1 and IKK Adhikari, A Xu, M Chen, ZJ Oncogene 26:3214-26 14633987 Pubmed 2003 Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling Ishitani, T Takaesu, G Ninomiya-Tsuji, J Shibuya, H Gaynor, RB Matsumoto, K EMBO J 22:6277-88 19675569 Pubmed 2009 Direct activation of protein kinases by unanchored polyubiquitin chains Xia, ZP Sun, L Chen, X Pineda, G Jiang, X Adhikari, A Zeng, W Chen, ZJ Nature inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of IKK-beta by TAK1 Phosphorylation of IKK-beta by TAK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764054 1 CHUK:IKBKB:IKBKG [cytosol] CHUK:IKBKB:IKBKG Reactome DB_ID: 9764052 1 UniProt:O88351 Ikbkb UniProt O88351 1 EQUAL 756 EQUAL Reactome DB_ID: 9763953 1 UniProt:O88522 Ikbkg UniProt O88522 1 EQUAL 419 EQUAL Reactome DB_ID: 9764050 1 UniProt:Q60680 Chuk UniProt Q60680 1 EQUAL 745 EQUAL Reactome Database ID Release 78 9764054 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=9764054 Reactome R-MMU-168113 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=R-MMU-168113.1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 9771380 1 p-S177,S181-IKKB:IKKA:NEMO [cytosol] p-S177,S181-IKKB:IKKA:NEMO Reactome DB_ID: 9763953 1 1 EQUAL 419 EQUAL Reactome DB_ID: 9764050 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9763965 1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 78 9771380 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=9771380 Reactome R-MMU-202513 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=R-MMU-202513.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9814024 Reactome Database ID Release 78 9814093 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=9814093 Reactome Database ID Release 78 9814095 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=9814095 Reactome R-MMU-2730876 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=R-MMU-2730876.1 In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex. <br>IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation. 14514672 Pubmed 2003 Signal-induced ubiquitination of I kappaB Kinase-beta Carter, Robert S Pennington, Kevin N Ungurait, Bradley J Arrate, Pia Ballard, Dean W J. Biol. Chem. 278:48903-6 20300203 Pubmed 2010 The IKK complex, a central regulator of NF-kappaB activation Israel, A Cold Spring Harb Perspect Biol 2:a000158 11460167 Pubmed 2001 TAK1 is a ubiquitin-dependent kinase of MKK and IKK Wang, C Deng, L Hong, M Akkaraju, GR Inoue, J Chen, ZJ Nature 412:346-51 17047224 Pubmed 2006 Regulation and function of IKK and IKK-related kinases Hacker, H Karin, M Sci STKE 2006:re13 11325957 Pubmed 2001 Persistent activation of NF-kappa B by the tax transforming protein involves chronic phosphorylation of IkappaB kinase subunits IKKbeta and IKKgamma Carter, R S Geyer, B C Xie, M Acevedo-Suárez, C A Ballard, D W J. Biol. Chem. 276:24445-8 inferred by electronic annotation IEA GO IEA 6.3.2.19 Ubiquitination of NEMO by TRAF6 Ubiquitination of NEMO by TRAF6 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 9764075 1 Reactome DB_ID: 9764139 1 Reactome DB_ID: 9771380 1 Reactome DB_ID: 9764075 1 Reactome DB_ID: 9771405 1 p-S177,S181-IKKB:IKKA:pUb-NEMO [cytosol] p-S177,S181-IKKB:IKKA:pUb-NEMO Reactome DB_ID: 9764050 1 1 EQUAL 745 EQUAL Reactome DB_ID: 9771403 1 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 321 (in Homo sapiens) 321 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 325 (in Homo sapiens) 325 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 326 (in Homo sapiens) 326 EQUAL ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at unknown position 1 EQUAL 419 EQUAL Reactome DB_ID: 9763965 1 O-phospho-L-serine at 177 (in Homo sapiens) 177 EQUAL O-phospho-L-serine at 181 (in Homo sapiens) 181 EQUAL 1 EQUAL 756 EQUAL Reactome Database ID Release 78 9771405 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=9771405 Reactome R-MMU-202562 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=R-MMU-202562.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9771360 Ub-TRAF6 trimer bound to CBM complex [plasma membrane] Ub-TRAF6 trimer bound to CBM complex Reactome DB_ID: 9771356 1 MALT1 trimer bound to Bcl10 and CARMA1 trimer [plasma membrane] MALT1 trimer bound to Bcl10 and CARMA1 trimer Reactome DB_ID: 9771354 1 MALT1 trimer [cytosol] MALT1 trimer Reactome DB_ID: 9771352 3 1 EQUAL 824 EQUAL Reactome Database ID Release 78 9771354 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=9771354 Reactome R-MMU-202487 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=R-MMU-202487.1 Reactome DB_ID: 9771349 1 Bcl10 trimer bound to CARMA1 trimer [plasma membrane] Bcl10 trimer bound to CARMA1 trimer Reactome DB_ID: 9771347 3 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 233 EQUAL Reactome DB_ID: 9771341 1 CARMA1 trimer [plasma membrane] CARMA1 trimer Reactome DB_ID: 9771054 1 PDK1:PIP2,PIP3 [plasma membrane] PDK1:PIP2,PIP3 Reactome DB_ID: 9758215 1 UniProt:Q9Z2A0 Pdpk1 UniProt Q9Z2A0 1 EQUAL 556 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 202277 1 PIP3, PI(3,4)P2 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PI(3,4,5)P3 [plasma membrane] PI(3,4)P2 [plasma membrane] ChEBI 16152 Reactome Database ID Release 78 9771054 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=9771054 Reactome R-MMU-202311 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=R-MMU-202311.1 Reactome DB_ID: 9771334 3 O-phospho-L-serine at 552 (in Homo sapiens) 552 EQUAL 1 EQUAL 1154 EQUAL Reactome Database ID Release 78 9771341 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=9771341 Reactome R-MMU-202445 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=R-MMU-202445.1 Reactome Database ID Release 78 9771349 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=9771349 Reactome R-MMU-202475 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=R-MMU-202475.1 Reactome Database ID Release 78 9771356 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=9771356 Reactome R-MMU-202468 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=R-MMU-202468.1 Reactome DB_ID: 9764065 3 ubiquitinylated lysine (K63-polyubiquitin [cytosol]) at 124 (in Homo sapiens) 124 EQUAL 1 EQUAL 522 EQUAL Reactome Database ID Release 78 9771360 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=9771360 Reactome R-MMU-202456 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=R-MMU-202456.1 Reactome Database ID Release 78 9771406 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=9771406 Reactome Database ID Release 78 9771408 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=9771408 Reactome R-MMU-202534 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=R-MMU-202534.1 During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009). 17728323 Pubmed 2007 Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti Sebban-Benin, H Pescatore, A Fusco, F Pascuale, V Gautheron, J Yamaoka, S Moncla, A Ursini, MV Courtois, G Hum Mol Genet 127: 19136968 Pubmed 2009 Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation Tokunaga, Fuminori Sakata, Shin-ichi Saeki, Yasushi Satomi, Yoshinori Kirisako, Takayoshi Kamei, Kiyoko Nakagawa, Tomoko Kato, Michiko Murata, Shigeo Yamaoka, Shoji Yamamoto, M Akira, Shizuo Takao, Toshifumi Tanaka, Keiji Iwai, Kazuhiro Nat. Cell Biol. 11:123-32 inferred by electronic annotation IEA GO IEA 2.7.11 p-S177,S181-IKKB:IKKA:pUb-NEMO phosphorylates IkB-alpha:NF-kB p-S177,S181-IKKB:IKKA:pUb-NEMO phosphorylates IkB-alpha:NF-kB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in React