BioPAX pathway converted from "Generation of second messenger molecules" in the Reactome database.

Generation of second messenger molecules

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 TBSMs in LAT

Reactome DB_ID: 113592

cytosolGO0005829

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

Reactomehttp://www.reactome.orgChEBI30616

Reactome DB_ID: 9679183

plasma membraneGO0005886

UniProt:O54957

Mus musculus

NCBI Taxonomy10090UniProtO54957

Chain Coordinates

EQUAL

262

EQUAL

Reactome DB_ID: 9679104

O4'-phospho-L-tyrosine at 161 (in Homo sapiens)

161

EQUAL

O4'-phospho-L-tyrosine [MOD:00048]

O4'-phospho-L-tyrosine at 200 (in Homo sapiens)

200

EQUAL

O4'-phospho-L-tyrosine at 220 (in Homo sapiens)

220

EQUAL

O4'-phospho-L-tyrosine at 255 (in Homo sapiens)

255

EQUAL

O4'-phospho-L-tyrosine at 156 (in Homo sapiens)

156

EQUAL

262

EQUAL

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9679079

Activated ZAP-70 [plasma membrane]

Activated ZAP-70

Reactome DB_ID: 9679058

Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4 [plasma membrane]

Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4

Reactome DB_ID: 9679056

T-cell receptor complex with phosphorylated ITAMs [plasma membrane]

T-cell receptor complex with phosphorylated ITAMs

Reactome DB_ID: 9679038

CD3 epsilon: CD3 delta with phosphorylated ITAMs [plasma membrane]

CD3 epsilon: CD3 delta with phosphorylated ITAMs

Reactome DB_ID: 9679036

UniProt:P04235

UniProtP04235

O4'-phospho-L-tyrosine at 149 (in Homo sapiens)

149

EQUAL

O4'-phospho-L-tyrosine at 160 (in Homo sapiens)

160

EQUAL

171

EQUAL

Reactome DB_ID: 9679032

UniProt:P22646

UniProtP22646

O4'-phospho-L-tyrosine at 188 (in Homo sapiens)

188

EQUAL

O4'-phospho-L-tyrosine at 199 (in Homo sapiens)

199

EQUAL

207

EQUAL

Reactome Database ID Release 709679038Database 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=9679038ReactomeR-MMU-202336

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-202336.1

Reactome DB_ID: 9677615

T-cell receptor [plasma membrane]

T-cell receptor

Converted from EntitySet in Reactome

Reactome DB_ID: 9677591

TCR chain alpha [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTRAC [plasma membrane]TRAV19 [plasma membrane]TRAV19 [plasma membrane]TCRA [plasma membrane]TRAV19 [plasma membrane]

UniProtA0A075B662UniProtA0A075B653UniProtA0A075B634UniProtA0A0B4J1K4UniProtA0A075B617Converted from EntitySet in Reactome

Reactome DB_ID: 9677613

TCR chain beta [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTRBV12-3 [plasma membrane]TRBV12-3 [plasma membrane]TRBC1 [plasma membrane]TRBC1 [plasma membrane]

UniProtA0A0B4J1H3UniProtA0A0A6YYE3UniProtA0A0A6YWV4UniProtA0A075B5J4Reactome Database ID Release 709677615Database 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=9677615ReactomeR-MMU-198183

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-198183.1

Reactome DB_ID: 9679054

CD3 zeta dimer with phosphorylated ITAMs [plasma membrane]

CD3 zeta dimer with phosphorylated ITAMs

Reactome DB_ID: 9679052

UniProt:P24161

UniProtP24161

O4'-phospho-L-tyrosine at 72 (in Homo sapiens)

EQUAL

O4'-phospho-L-tyrosine at 83 (in Homo sapiens)

EQUAL

O4'-phospho-L-tyrosine at 111 (in Homo sapiens)

111

EQUAL

O4'-phospho-L-tyrosine at 123 (in Homo sapiens)

123

EQUAL

O4'-phospho-L-tyrosine at 142 (in Homo sapiens)

142

EQUAL

O4'-phospho-L-tyrosine at 153 (in Homo sapiens)

153

EQUAL

164

EQUAL

Reactome Database ID Release 709679054Database 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=9679054ReactomeR-MMU-202303

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-202303.1

Reactome DB_ID: 9679044

CD3 epsilon: CD3 gamma with phosphorylated ITAM [plasma membrane]

CD3 epsilon: CD3 gamma with phosphorylated ITAM

Reactome DB_ID: 9679032

O4'-phospho-L-tyrosine at 188 (in Homo sapiens)

188

EQUAL

O4'-phospho-L-tyrosine at 199 (in Homo sapiens)

199

EQUAL

207

EQUAL

Reactome DB_ID: 9679042

UniProt:P11942

UniProtP11942

O4'-phospho-L-tyrosine at 160 (in Homo sapiens)

160

EQUAL

O4'-phospho-L-tyrosine at 171 (in Homo sapiens)

171

EQUAL

182

EQUAL

Reactome Database ID Release 709679044Database 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=9679044ReactomeR-MMU-202167

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-202167.1Reactome Database ID Release 709679056Database 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=9679056ReactomeR-MMU-203493

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-203493.1

Reactome DB_ID: 9678992

UniProt:P06332

UniProtP06332

EQUAL

458

EQUAL

Reactome DB_ID: 9679026

MHC Class II bearing antigen peptide [plasma membrane]

MHC Class II bearing antigen peptide

Reactome DB_ID: 173548

Antigen [plasma membrane]

Antigen

Reactome DB_ID: 9679024

MHC class II alpha/beta dimer [plasma membrane]

MHC class II alpha/beta dimer

Converted from EntitySet in Reactome

Reactome DB_ID: 9679004

HLA II alpha chain [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHLA class II histocompatibility antigen, DR alpha chain precursor [plasma membrane]HLA class II histocompatibility antigen, DQ [plasma membrane]

UniProtP01904UniProtP01910Converted from EntitySet in Reactome

Reactome DB_ID: 9679022

HLA II beta chain [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHLA class II histocompatibility antigen, DQ beta 2 chain [plasma membrane]HLA class II histocompatibility antigen, DR beta 4 chain [plasma membrane]HLA class II histocompatibility antigen, DQ [plasma membrane]HLA class II histocompatibility antigen, DR beta 4 chain [plasma membrane]

UniProtP01921UniProtQ3UUV9UniProtP04230Reactome Database ID Release 709679024Database 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=9679024ReactomeR-MMU-2213189

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-2213189.1Reactome Database ID Release 709679026Database 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=9679026ReactomeR-MMU-203463

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-203463.1

Reactome DB_ID: 9678988

UniProt:P06240 Lck

Lck

LckLsk-tFUNCTION Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP (By similarity). Interacts with UNC119; this interaction plays a crucial role in activation of LCK (By similarity).ACTIVITY REGULATION The relative activities of the inhibitory tyrosine-protein kinase CSK and the activating tyrosine-protein phosphatase PTPRC/CD45 determine the level of LCK activity. These interactions allow rapid and efficient activation of LCK in response to TCR stimulation (By similarity).SUBUNIT Binds to the cytoplasmic domain of cell surface receptors, such as AXL, CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to effector molecules, such as PI4K, VAV1, RASA1, FYB1 and to other protein kinases including CDK1, RAF1, ZAP70 and SYK. Binds to phosphatidylinositol 3'-kinase (PI3K) from T-lymphocytes through its SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70 through its SH2 domain. Interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH. Interacts with RUNX3. Forms a signaling complex with EPHA1, PTK2B AND PI3-KINASE; upon activation by EFNA1 which may regulate T-lymphocytes migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylation in the presence of functional ZAP70. Interacts with CEACAM1 (via cytoplasmic domain); mediates CEACAM1 phosphorylation resulting in PTPN6 recruitment that dephosphorylates TCR stimulation-induced CD247 and ZAP70. Interacts with FYB2 (By similarity). Interacts with CD160.TISSUE SPECIFICITY Present at a low level in most T-cells, and at an elevated level in LSTRA and Thy19 (T-cell lymphoma) cells.DEVELOPMENTAL STAGE Levels remain relatively constant throughout T-cell ontogeny.DOMAIN The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation (By similarity).PTM Autophosphorylated on Tyr-394, increasing enzymatic activity, this site is dephosphorylated by PTN22. Phosphorylated on Tyr-505 by CSK, decreasing activity. Dephosphorylated by PTPRC/CD45. Dephosphorylation at Tyr-394 by PTPN2 negatively regulates T-cells differentiation (By similarity).PTM Myristoylation is required prior to palmitoylation.PTM Palmitoylation regulates subcellular location.DISRUPTION PHENOTYPE Mice show a dramatic reduction in the level of peripheral T-cells, with 5-10% of wild-type levels. T-cells also exhibit a 10-fold decrease in proliferative response.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.

UniProtP06240

O4'-phospho-L-tyrosine at 394 (in Homo sapiens)

394

EQUAL

509

EQUAL

Reactome Database ID Release 709679058Database 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=9679058ReactomeR-MMU-203494

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-203494.1

Reactome DB_ID: 9679077

UniProt:P43404

UniProtP43404

O4'-phospho-L-tyrosine at 493 (in Homo sapiens)

493

EQUAL

O4'-phospho-L-tyrosine at 315 (in Homo sapiens)

315

EQUAL

619

EQUAL

Reactome Database ID Release 709679079Database 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=9679079ReactomeR-MMU-202181

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-202181.1GO0004713

GO molecular function

Reactome Database ID Release 709679147Database 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=9679147Reactome Database ID Release 709679185Database 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=9679185ReactomeR-MMU-202245

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-202245.1The adaptor molecule LAT (Linker for the Activation of T cells) is a membrane protein that links the TCR signal to the cell activation. It has a total 10 (Y36, Y45, Y64, Y110, Y156, Y161, Y200, Y220, and Y255) conserved TBSMs (tyrosine based signaling motifs) in its cytoplasmic region. These tyrosine residues are phosphorylated by the activated ZAP-70 upon TCR/CD3 complex engagement. Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domains of other proteins, including PLC-gamma1, Grb2 and Gads, and indirectly binds SOS, Vav, SLP-76, and Itk. The residues Y200, Y220 and Y255 are responsible for Grb2 binding, Y200 and Y220 but not Y255, are necessary for Gads binding and Y161 for the PLC-gamma1 binding (numbering based on Uniprot isoform 1).

11752630Pubmed2000LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathwaysWange, RLSci STKE 2000:RE110811803Pubmed2000Association 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, WTrible, RPZhu, MLiu, SKMcGlade, CJSamelson, LEJ Biol Chem 275:23355-6114510693Pubmed2003Hematopoietic adaptors in T-cell signaling: potential applications to transplantationRudd, CEWang, HAm J Transplant 3:1204-10inferred by electronic annotationIEAGOIEA

Recruitment of Gads to LAT

Reactome DB_ID: 9679134

UniProt:O89100

UniProtO89100

EQUAL

330

EQUAL

Reactome DB_ID: 9679104

O4'-phospho-L-tyrosine at 161 (in Homo sapiens)

161

EQUAL

O4'-phospho-L-tyrosine at 200 (in Homo sapiens)

200

EQUAL

O4'-phospho-L-tyrosine at 220 (in Homo sapiens)

220

EQUAL

O4'-phospho-L-tyrosine at 255 (in Homo sapiens)

255

EQUAL

O4'-phospho-L-tyrosine at 156 (in Homo sapiens)

156

EQUAL

262

EQUAL

Reactome DB_ID: 9679136

GADS:p-5Y-LAT [plasma membrane]

GADS:p-5Y-LAT

Reactome DB_ID: 9679134

EQUAL

330

EQUAL

Reactome DB_ID: 9679104

O4'-phospho-L-tyrosine at 161 (in Homo sapiens)

161

EQUAL

O4'-phospho-L-tyrosine at 200 (in Homo sapiens)

200

EQUAL

O4'-phospho-L-tyrosine at 220 (in Homo sapiens)

220

EQUAL

O4'-phospho-L-tyrosine at 255 (in Homo sapiens)

255

EQUAL

O4'-phospho-L-tyrosine at 156 (in Homo sapiens)

156

EQUAL

262

EQUAL

Reactome Database ID Release 709679136Database 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=9679136ReactomeR-MMU-202177

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-202177.1Reactome Database ID Release 709679223Database 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=9679223ReactomeR-MMU-202325

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-202325.1Gads is a member of the Grb2 family containing SH2 and SH3 domains with the arrangement SH3-SH2-SH3. Gads binds to the tyrosine phosphorylated residues Y171 and Y191 of LAT through its SH2 domain. It plays a critical role in signaling from the T cell receptor by promoting the formation of a complex between SLP-76 and LAT.

11607830Pubmed2001The role of Gads in hematopoietic cell signallingLiu, SKBerry, DMMcGlade, CJOncogene 20:6284-90inferred by electronic annotationIEAGOIEA

Recruitment of SLP-76 to Gads

Reactome DB_ID: 430203

UniProt:Q60787 Lcp2

Lcp2

Lcp2FUNCTION 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).

UniProtQ60787

EQUAL

533

EQUAL

Reactome DB_ID: 9679136

Reactome DB_ID: 9679139

SLP-76 bound to Gads:LAT [plasma membrane]

SLP-76 bound to Gads:LAT

Reactome DB_ID: 430203

EQUAL

533

EQUAL

Reactome DB_ID: 9679136

Reactome Database ID Release 709679139Database 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=9679139ReactomeR-MMU-202151

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-202151.1Reactome Database ID Release 709679181Database 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=9679181ReactomeR-MMU-202241

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-202241.1SLP-76 is an adaptor protein that links proximal and distal T cell receptor signaling events through its function as a molecular scaffold in the assembly of multi molecular signaling complexes. SLP-76 consists of three domains that mediate interactions with many different signaling proteins: an N-terminal acidic domain containing three tyrosine phosphorylation sites, a large central proline-rich region, and a C-terminal SH2 domain. The function of SLP-76 is dependent on its association with Gads. SLP-76 constitutively binds through its 'RxxK' motif in the proline rich region to the SH3 domain of Gads upon TCR activation.

inferred by electronic annotationIEAGOIEA

2.7.10

Phosphorylation of SLP-76

Reactome DB_ID: 9679139

Reactome DB_ID: 113592

Reactome DB_ID: 9679146

p-Y113,128,145-SLP-76:GADS:LAT [plasma membrane]

p-Y113,128,145-SLP-76:GADS:LAT

Reactome DB_ID: 9679144

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

533

EQUAL

Reactome DB_ID: 9679136

Reactome Database ID Release 709679146Database 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=9679146ReactomeR-MMU-202162

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-202162.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9679079

Reactome Database ID Release 709679149Database 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=9679149ReactomeR-MMU-202216

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-202216.1Once SLP-76 is recruited to Gads its rapidly phosphorylated on the tyrosine residues in the N-terminal acidic domain. This domain contains three tyrosine phosphorylation sites, Y113, Y128 and Y145. These tyrosine residues are phosphorylated by tyrosine kinase ZAP-70 and these phosphorylated tyrosine residues provide the binding site for the SH2 domains of the incoming signaling proteins like Vav, Itk and PLC-gamma1.

17652306Pubmed2007Keeping the (kinase) party going: SLP-76 and ITK dance to the beatQi, QAugust, ASci STKE 2007:pe39inferred by electronic annotationIEAGOIEA

Recruitment of ITK to SLP-76

Reactome DB_ID: 9679146

Reactome DB_ID: 9679200

UniProt:Q03526 Itk

Itk

ItkTlkEmtTskFUNCTION Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Phosphorylates TBX21 at 'Tyr-525' and mediates its interaction with GATA3 (PubMed:15662016).SUBUNIT Homooligomerizes; this association negatively regulates kinase activity. Interacts with PPIA/CYPA; this interaction regulates TCR signal strength via a proline-directed conformational switch in ITK. Interacts with THEMIS (By similarity). Interacts with FASLG. Interacts with VAV1; this interaction is important for VAV1 localization and TCR-induced actin polarization. Interacts with TBX21 (PubMed:15662016).TISSUE SPECIFICITY Is detected in the thymus, lymph node and very faintly in the spleen, but is not detected in the liver, lung, kidney, heart, brain, intestine or testis. Expressed in T-lymphocytes and mast cells. It may also be expressed in natural killer cells.DEVELOPMENTAL STAGE Is present in the fetal thymus as early as day 14 of gestation. The levels are 5- to 10-fold higher in thymocytes than in peripheral T-cells, and increase in the thymus during development from neonate to adult.INDUCTION Through a myriad of surface receptors including the TCR/CD3 signaling complex, coreceptors, or chemokine receptors.DOMAIN The N-terminal PH domain allows ITK to be recruited to the plasma membrane by an activated PI3 kinase. This domain contains also a proline-rich region (PRR). The adjoining domain is a SH3 domain, which binds to PRR (from itself or from other proteins). Next, a SH2 domain is required for binding tyrosine-phosphorylated substrates. In the C-terminal region, the kinase domain is required for tyrosine phosphorylation (By similarity).PTM Phosphorylated at Tyr-517 in the activation loop of the kinase domain by LCK. Subsequent autophosphorylation at Tyr-186 leads to the kinase activation. The autophosphorylated Tyr-186 lies within the substrate binding sequence of the SH3 domain (By similarity).PTM Ubiquitinated.DISRUPTION PHENOTYPE Mice display decreased mature thymocytes and elicit profound defect in CD4+ and CD8+ T-cell development. Additionally, they show a strong decrease of cytokine production in response to TCR receptor stimulation.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.

UniProtQ03526

EQUAL

620

EQUAL

Reactome DB_ID: 9679202

ITK:p-Y113,128,145-SLP-76:GADS:LAT [plasma membrane]

ITK:p-Y113,128,145-SLP-76:GADS:LAT

Reactome DB_ID: 9679146

Reactome DB_ID: 9679200

EQUAL

620

EQUAL

Reactome Database ID Release 709679202Database 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=9679202ReactomeR-MMU-202359

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-202359.1Reactome Database ID Release 709679240Database 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=9679240ReactomeR-MMU-202375

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-202375.1ITK is a member of the Tec protein tyrosine kinase family which forms a complex with SLP-76 after TCR activation. ITK has N-terminal pleckstrin homology (PH) domain, a Tec homology (TH) domain, a proline rich domain, a SH3 domain, an SH2 domain and a C-term kinase domain. The SH2 domain of ITK may interact with Y145 within the N-ter acidic domain of SLP-76 and the SH3 domain of the ITK binds the proline rich region of SLP-76. ITK plays an important role in phosphorylating and activating PLC-gamma-1, leading to the development of second-messenger molecules.

inferred by electronic annotationIEAGOIEA

Recruitment of PLC-gamma1 to SLP-76

Reactome DB_ID: 9679146

Reactome DB_ID: 9679095

UniProt:Q62077 Plcg1

Plcg1

Plcg-1Plcg1FUNCTION Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Plays an important role in the regulation of intracellular signaling cascades. Becomes activated in response to ligand-mediated activation of receptor-type tyrosine kinases, such as PDGFRA, PDGFRB, FGFR1, FGFR2, FGFR3 and FGFR4. Plays a role in actin reorganization and cell migration.ACTIVITY REGULATION Activated by phosphorylation on tyrosine residues.SUBUNIT Interacts (via SH2 domain) with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated). Interacts with RALGPS1. Interacts (via SH2 domains) with VIL1 (phosphorylated at C-terminus tyrosine phosphorylation sites). Interacts (via SH2 domain) with RET (By similarity). Interacts with AGAP2 via its SH3 domain. Interacts with LAT (phosphorylated) upon TCR activation. Interacts (via SH3 domain) with the Pro-rich domain of TNK1. Associates with BLNK, VAV1, GRB2 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with CBLB in activated T-cells; which inhibits phosphorylation. Interacts with SHB. Interacts (via SH3 domain) with the Arg/Gly-rich-flanked Pro-rich domains of KHDRBS1/SAM68. This interaction is selectively regulated by arginine methylation of KHDRBS1/SAM68. Interacts with INPP5D/SHIP1, THEMIS and CLNK. Interacts with FLT4 and KIT. Interacts with AXL (By similarity). Interacts with SYK; activates PLCG1 (By similarity). Interacts with FLT1 (tyrosine-phosphorylated). Interacts (via SH2 domain) with PDGFRA and PDGFRB (tyrosine phosphorylated). Interacts with PIP5K1C. Interacts with NTRK1 and NTRK2 (phosphorylated upon ligand-binding). Interacts with TESPA1 (By similarity). Interacts with GRB2, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1.DOMAIN The SH3 domain mediates interaction with RALGPS1 (By similarity). The SH3 domain also mediates interaction with CLNK.PTM Tyrosine phosphorylated in response to signaling via activated FLT3, KIT and PDGFRA (By similarity). Tyrosine phosphorylated by activated FGFR1, FGFR2, FGFR3 and FGFR4. Tyrosine phosphorylated by activated FLT1 and KDR. Tyrosine phosphorylated by activated PDGFRB. The receptor-mediated activation of PLCG1 involves its phosphorylation by tyrosine kinases in response to ligation of a variety of growth factor receptors and immune system receptors. For instance, SYK phosphorylates and activates PLCG1 in response to ligation of the B-cell receptor. Phosphorylated by ITK and TXK on Tyr-783 upon TCR activation in T-cells. May be dephosphorylated by PTPRJ (By similarity).PTM Ubiquitinated by CBLB in activated T-cells.

UniProtQ62077

EQUAL

1290

EQUAL

Reactome DB_ID: 9679187

PLCG1:p-3Y-SLP-76:Gads:LAT [plasma membrane]

PLCG1:p-3Y-SLP-76:Gads:LAT

Reactome DB_ID: 9679146

Reactome DB_ID: 9679095

EQUAL

1290

EQUAL

Reactome Database ID Release 709679187Database 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=9679187ReactomeR-MMU-202279

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-202279.1Reactome Database ID Release 709679227Database 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=9679227ReactomeR-MMU-202331

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-202331.1PLC-gamma1 plays an important role in transducing the external signal in to second messengers by hydrolysing PIP2. PLC-gamma1 contains an N-term PH domain, a catalytic domain 'X' followed by two SH2 domains and an SH3 domain, a C-term catalytic domain 'Y' and a C2 domain (Ca++ binding). PLC-gamma1 interacts with both SLP-76 aswell as LAT. It interacts with its SH3 domain to the proline rich sequence of SLP-76. This interaction aids in localizing PLC-gamma1 to the membrane. This recruitment of PLC-gamma1 to LAT and SLP-76 is essential for its TCR induced tyrosine phosphorylation and activation.

11048639Pubmed2000The mechanism of phospholipase C-gamma1 regulationKim, MJKim, ERyu, SHSuh, PGExp Mol Med 32:101-911390650Pubmed2001Identification 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 NFATYablonski, DKadlecek, TWeiss, AMol Cell Biol 21:4208-18inferred by electronic annotationIEAGOIEA

Recruitment of PLC-gamma1 to LAT

Reactome DB_ID: 9679104

O4'-phospho-L-tyrosine at 161 (in Homo sapiens)

161

EQUAL

O4'-phospho-L-tyrosine at 200 (in Homo sapiens)

200

EQUAL

O4'-phospho-L-tyrosine at 220 (in Homo sapiens)

220

EQUAL

O4'-phospho-L-tyrosine at 255 (in Homo sapiens)

255

EQUAL

O4'-phospho-L-tyrosine at 156 (in Homo sapiens)

156

EQUAL

262

EQUAL

Reactome DB_ID: 9679095

EQUAL

1290

EQUAL

Reactome DB_ID: 9679106

PLCG1:p-5Y-LAT [plasma membrane]

PLCG1:p-5Y-LAT

Reactome DB_ID: 9679104

O4'-phospho-L-tyrosine at 161 (in Homo sapiens)

161

EQUAL

O4'-phospho-L-tyrosine at 200 (in Homo sapiens)

200

EQUAL

O4'-phospho-L-tyrosine at 220 (in Homo sapiens)

220

EQUAL

O4'-phospho-L-tyrosine at 255 (in Homo sapiens)

255

EQUAL

O4'-phospho-L-tyrosine at 156 (in Homo sapiens)

156

EQUAL

262

EQUAL

Reactome DB_ID: 9679095

EQUAL

1290

EQUAL

Reactome Database ID Release 709679106Database 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=9679106ReactomeR-MMU-202240

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-202240.1Reactome Database ID Release 709679108Database 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=9679108ReactomeR-MMU-202212

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-202212.1PLC-gamma1 interacts with its SH2 domain to the pY132 residue of LAT.

inferred by electronic annotationIEAGOIEA

2.7.10

Phosphorylation of PLC-gamma1

Converted from EntitySet in Reactome

Reactome DB_ID: 9679189

PLC-gamma1 bound to LAT or SLP-76 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 9679197

Phosphorylated PLC-gamma1 bound to LAT or SLP-76 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 9679204

ZAP-70 and ITK tyrosine kinases [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome Database ID Release 709679205Database 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=9679205Reactome Database ID Release 709679211Database 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=9679211ReactomeR-MMU-202248

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-202248.1Three tyrosine residues at positions 771, 783 and 1254 in PLC-gamma1 have been identified as the sites of receptor tyrosine kinase phosphorylation. Of these Y783 and Y1254 are required for activation of PLC-gamma1. The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK.

inferred by electronic annotationIEAGOIEA

INHIBITION

Reactome Database ID Release 709679212Database 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=9679212

Reactome DB_ID: 9679209

UniProt:A8E0Y8

UniProtA8E0Y8

EQUAL

1021

EQUAL

Disassociation of PLC-gamma1 from LAT

Reactome DB_ID: 9679193

phosphorylated PLC-gamma1 bound to LAT [plasma membrane]

phosphorylated PLC-gamma1 bound to LAT

Reactome DB_ID: 9679191

O4'-phospho-L-tyrosine at 771

771

EQUAL

O4'-phospho-L-tyrosine at 783

783

EQUAL

O4'-phospho-L-tyrosine at 1253

1253

EQUAL

1290

EQUAL

Reactome DB_ID: 9679104

O4'-phospho-L-tyrosine at 161 (in Homo sapiens)

161

EQUAL

O4'-phospho-L-tyrosine at 200 (in Homo sapiens)

200

EQUAL

O4'-phospho-L-tyrosine at 220 (in Homo sapiens)

220

EQUAL

O4'-phospho-L-tyrosine at 255 (in Homo sapiens)

255

EQUAL

O4'-phospho-L-tyrosine at 156 (in Homo sapiens)

156

EQUAL

262

EQUAL

Reactome Database ID Release 709679193Database 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=9679193ReactomeR-MMU-202310

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-202310.1

Reactome DB_ID: 9679191

O4'-phospho-L-tyrosine at 771

771

EQUAL

O4'-phospho-L-tyrosine at 783

783

EQUAL

O4'-phospho-L-tyrosine at 1253

1253

EQUAL

1290

EQUAL

Reactome DB_ID: 9679104

O4'-phospho-L-tyrosine at 161 (in Homo sapiens)

161

EQUAL

O4'-phospho-L-tyrosine at 200 (in Homo sapiens)

200

EQUAL

O4'-phospho-L-tyrosine at 220 (in Homo sapiens)

220

EQUAL

O4'-phospho-L-tyrosine at 255 (in Homo sapiens)

255

EQUAL

O4'-phospho-L-tyrosine at 156 (in Homo sapiens)

156

EQUAL

262

EQUAL

Reactome Database ID Release 709681701Database 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=9681701ReactomeR-MMU-213406

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-213406.1The activated PLC-gamma1 detaches from its substrate LAT and translocates to the membrane.

inferred by electronic annotationIEAGOIEA

Disassociation of PLC-gamma1 from SLP-76

Reactome DB_ID: 9679195

phosphorylated PLC-gamma1 bound to SLP-76 [plasma membrane]

phosphorylated PLC-gamma1 bound to SLP-76

Reactome DB_ID: 9679146

Reactome DB_ID: 9679191

O4'-phospho-L-tyrosine at 771

771

EQUAL

O4'-phospho-L-tyrosine at 783

783

EQUAL

O4'-phospho-L-tyrosine at 1253

1253

EQUAL

1290

EQUAL

Reactome Database ID Release 709679195Database 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=9679195ReactomeR-MMU-202302

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-202302.1

Reactome DB_ID: 9679146

Reactome DB_ID: 9679191

O4'-phospho-L-tyrosine at 771

771

EQUAL

O4'-phospho-L-tyrosine at 783

783

EQUAL

O4'-phospho-L-tyrosine at 1253

1253

EQUAL

1290

EQUAL

Reactome Database ID Release 709681703Database 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=9681703ReactomeR-MMU-213407

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-213407.1The activated PLC-gamma1 detaches from its substrate SLP-76 and translocates to the membrane.

inferred by electronic annotationIEAGOIEA

Translocation of PLC-gamma1 to PIP2

Reactome DB_ID: 9679191

O4'-phospho-L-tyrosine at 771

771

EQUAL

O4'-phospho-L-tyrosine at 783

783

EQUAL

O4'-phospho-L-tyrosine at 1253

1253

EQUAL

1290

EQUAL

Reactome DB_ID: 179856

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate

PIP2

ChEBI18348

Reactome DB_ID: 9679233

Activated PLC gamma1 bound to PIP2 [plasma membrane]

Activated PLC gamma1 bound to PIP2

Reactome DB_ID: 179856

Reactome DB_ID: 9679231

O4'-phospho-L-tyrosine at 472

472

EQUAL

O4'-phospho-L-tyrosine at 771

771

EQUAL

O4'-phospho-L-tyrosine at 783

783

EQUAL

O4'-phospho-L-tyrosine at 1253

1253

EQUAL

1290

EQUAL

Reactome Database ID Release 709679233Database 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=9679233ReactomeR-MMU-202269

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-202269.1Reactome Database ID Release 709679235Database 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=9679235ReactomeR-MMU-202354

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-202354.1Activated PLA-gamma1 translocates to the plasmamembrane and interacts with the inositol ring of the membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2) with its PH domain.

inferred by electronic annotationIEAGOIEA

3.1.4.11

PLC-gamma1 hydrolyses PIP2

Reactome DB_ID: 29356

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 179856

Reactome DB_ID: 114520

1D-myo-inositol 1,4,5-trisphosphate [ChEBI:16595]

1D-myo-inositol 1,4,5-trisphosphate

ChEBI16595

Reactome DB_ID: 112275

diglyceride [ChEBI:18035]

diglyceride

ChEBI18035PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9679233

GO0004435

GO molecular function

Reactome Database ID Release 709679248Database 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=9679248Reactome Database ID Release 709679250Database 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=9679250ReactomeR-MMU-202407

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-202407.1On recruitment to plasma membrane PLC-gamma1 then hydrolyses PIP2 producing two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 induces a transient increase in intracellular free Ca++, while DAG is a direct activator of protein kinase C (PKC theta). These process have been implicated in many cellular physiological functions like cell proliferation, cell growth and differentiation.

inferred by electronic annotationIEAGOIEA

p-SLP-76 binds ADAP

Reactome DB_ID: 9679144

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

533

EQUAL

Reactome DB_ID: 9689834

UniProt:O35601 Fyb1

Fyb1

Fyb1FybFUNCTION May play a role in linking T-cell signaling to remodeling of the actin cytoskeleton (By similarity). Acts as an adapter protein of the FYN and LCP2 signaling cascades in T-cells. Modulates the expression of interleukin-2 (IL-2). Involved in platelet activation. Prevents the degradation of SKAP1 and SKAP2.SUBUNIT Interacts with FYN, LCP2, SKAP1 and SKAP2. Part of a complex consisting of SKAP2, FYB1 and PTPNS1. Part of a complex consisting of SKAP2, FYB1 and LILRB3. Interacts with FASLG. Interacts with EVL (By similarity). Interacts with TMEM47 (PubMed:21881001). Interacts with LCK (By similarity).TISSUE SPECIFICITY Expressed in hematopoietic tissues such as myeloid and T-cells, spleen and thymus. Not expressed in B-cells, nor in non-lymphoid tissues. FYB-130 is preferentially expressed in mature T-cells compared to FYB-120, whereas thymocytes showed a greater relative amount of FYB-120. Expressed in podocytes.PTM T-cell receptor ligation leads to increased tyrosine phosphorylation.DISRUPTION PHENOTYPE Slight defects in platelet function.

UniProtO35601

EQUAL

783

EQUAL

Reactome DB_ID: 9693164

p-SLP-76:ADAP [cytosol]

p-SLP-76:ADAP

Reactome DB_ID: 9679144

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

533

EQUAL

Reactome DB_ID: 9689834

EQUAL

783

EQUAL

Reactome Database ID Release 709693164Database 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=9693164ReactomeR-MMU-430124

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-430124.1Reactome Database ID Release 709693166Database 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=9693166ReactomeR-MMU-430135

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-430135.1SLP-76 inducibly-associates with ADAP (also known as FYN-binding protein or SLAP-130) a hematopoietic-specific adapter protein. ADAP has been implicated in T cell migration and rearrangement of the actin cytoskeleton. In platelets, adhesion to fibrinogen stimulates the association of SLP-76 with ADAP and VASP (Obergfell et al. 2001). ADAP knockout mice exhibit mild thrombocytopenia (Kasirer-Friede et al. 2007).

17003372Pubmed2007ADAP is required for normal alphaIIbbeta3 activation by VWF/GP Ib-IX-V and other agonistsKasirer-Friede, AMoran, BNagrampa-Orje, JSwanson, KRuggeri, ZMSchraven, BNeel, BGKoretzky, GShattil, Sanford JBlood 109:1018-259115214Pubmed1997Molecular cloning of SLAP-130, an SLP-76-associated substrate of the T cell antigen receptor-stimulated protein tyrosine kinasesMusci, MAHendricks-Taylor, LRMotto, DGPaskind, MKamens, JTurck, CWKoretzky, GAJ Biol Chem 272:11674-711113155Pubmed2001The molecular adapter SLP-76 relays signals from platelet integrin alphaIIbbeta3 to the actin cytoskeletonObergfell, AJudd, BAdel Pozo, MASchwartz, MAKoretzky, GAShattil, Sanford JJ Biol Chem 276:5916-2311567141Pubmed2001Coupling of the TCR to integrin activation by Slap-130/FybPeterson, EJWoods, MLDmowski, SADerimanov, GJordan, MSWu, JNMyung, PSLiu, QHPribila, JTFreedman, BDShimizu, YKoretzky, GAScience 293:2263-510747096Pubmed2000Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeletonKrause, MSechi, ASKonradt, MMonner, DGertler, FBWehland, JJ Cell Biol 149:181-9410671560Pubmed2000Functional association between SLAP-130 and SLP-76 in Jurkat T cellsBoerth, NJJudd, BAKoretzky, GAJ Biol Chem 275:5143-52inferred by electronic annotationIEAGOIEA

p-SLP-76 binds NCK

Reactome DB_ID: 9679144

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

533

EQUAL

Reactome DB_ID: 9683317

UniProt:Q99M51

UniProtQ99M51

EQUAL

377

EQUAL

Reactome DB_ID: 9693174

p-SLP-76:NCK1 [cytosol]

p-SLP-76:NCK1

Reactome DB_ID: 9679144

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

533

EQUAL

Reactome DB_ID: 9683317

EQUAL

377

EQUAL

Reactome Database ID Release 709693174Database 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=9693174ReactomeR-MMU-430188

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-430188.1Reactome Database ID Release 709693187Database 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=9693187ReactomeR-MMU-430190

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-430190.1SLP-76 interacts with the adaptor protein NCK1. This interaction involved the SH2 domain of NCK1, leaving 3 three SH3 domains free to interact with other proteins, notably PAK1, N-WASP and Sos.

9846482Pubmed1998Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76Bubeck Wardenburg, JPappu, RBu, JYMayer, BChernoff, JStraus, DChan, ACImmunity 9:607-16inferred by electronic annotationIEAGOIEA

NCK binds PAK

Reactome DB_ID: 9693174

Converted from EntitySet in Reactome

Reactome DB_ID: 9689443

PAK1,2,3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPAK1 [cytosol]Pak3 [cytosol]PAK2 [cytosol]

UniProtO88643UniProtQ61036UniProtQ8CIN4

Reactome DB_ID: 9693183

p-SLP-76:NCK:PAK [cytosol]

p-SLP-76:NCK:PAK

Reactome DB_ID: 9693174

Converted from EntitySet in Reactome

Reactome DB_ID: 9689443

Reactome Database ID Release 709693183Database 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=9693183ReactomeR-MMU-430189

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-430189.1Reactome Database ID Release 709693185Database 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=9693185ReactomeR-MMU-430183

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-430183.1NCK binds to PAK through its second SH3 domain. PAK interacts with NCK via the amino terminal SH3 binding domain. This interaction leads to the phosphorylation of NCK at multiple sites.

8824201Pubmed1996Interaction of the Nck adapter protein with p21-activated kinase (PAK1)Bokoch, GMWang, YBohl, BPSells, MAQuilliam, LAKnaus, UGJ Biol Chem 271:25746-98798379Pubmed1996The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1Galisteo, MLChernoff, JSu, YCSkolnik, EYSchlessinger, JJ Biol Chem 271:20997-1000inferred by electronic annotationIEAGOIEA

NCK recruits WASP

Reactome DB_ID: 9693174

Reactome DB_ID: 9693177

UniProt:P70315 Was

Was

WasWaspFUNCTION Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function. Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria. In addition to its role in the cytoplasmic cytoskeleton, also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. Promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs).SUBUNIT Binds the Arp2/3 complex (By similarity). Interacts with CDC42, RAC, NCK, HCK, FYN, SRC kinase FGR, BTK, ABL1, PSTPIP1, WIP, and to the p85 subunit of PLC-gamma (PubMed:9488710). Interacts (via C-terminus) with ALDOA (By similarity). Interacts with NCK1 (via SH3 domains) (PubMed:8910519). Interacts with FCHSD2 (PubMed:23437151).DOMAIN The WH1 (Wasp homology 1) domain may bind a Pro-rich ligand.DOMAIN The CRIB (Cdc42/Rac-interactive-binding) region binds to the C-terminal WH2 domain in the autoinhibited state of the protein. Binding of Rho-type GTPases to the CRIB induces a conformation change and leads to activation.PTM Phosphorylated at Tyr-293 by FYN and HCK, inducing WAS effector activity after TCR engagement. Phosphorylation at Tyr-293 enhances WAS activity in promoting actin polymerization and filopodia formation.

UniProtP70315

EQUAL

502

EQUAL

Reactome DB_ID: 9693179

p-SLP-76:NCK1:WASP [cytosol]

p-SLP-76:NCK1:WASP

Reactome DB_ID: 9693174

Reactome DB_ID: 9693177

EQUAL

502

EQUAL

Reactome Database ID Release 709693179Database 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=9693179ReactomeR-MMU-430186

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-430186.1Reactome Database ID Release 709693181Database 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=9693181ReactomeR-MMU-430180

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-430180.1The second SH3 domain of NCK interacts with the carboxy-terminal SH3 domain of WASP. WASP family proteins bind the Arp2/3 complex, stimulating its ability to nucleate actin filaments and induce filament branching.

10679362Pubmed2000How WASP-family proteins and the Arp2/3 complex convert intracellular signals into cytoskeletal structuresMullins, RDCurr Opin Cell Biol 12:91-67565724Pubmed1995Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domainsRivero-Lezcano, OMMarcilla, ASameshima, JHRobbins, KCMol Cell Biol 15:5725-31inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 709770499Database 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=9770499ReactomeR-MMU-202433

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-202433.1In addition to serving as a scaffold via auto-phosphorylation, ZAP-70 also phosphorylates a restricted set of substrates following TCR stimulation - including LAT and SLP-76. These substrates have been recognized to play pivotal role in TCR signaling by releasing second messengers. When phosphorylated, LAT and SLP-76 act as adaptor proteins which serve as nucleation points for the construction of a higher order signalosome: GADS, PLC-gamma1 and GRB2 bind to the LAT on the phosphorylated tyrosine residues (steps 8 and 13). SLP-76 and SOS are then moved to the signalosome by interacting with the SH3 domains of GRB2 and GADS via their proline rich sequences (step 9). Three SLP-76 acidic domain N-term tyrosine residues are phosphorylated by ZAP-70, once SLP-76 binds to GADS (step 10). These phospho-tyrosine residues act as binding sites to the SH2 domains of PLC-gamma1, Vav and Itk (steps 11 and 12). <p>PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by Itk and ZAP-70 (step 14). Phosphorylated PLC-gamma1 subsequently detaches from LAT and SLP-76 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 15). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3. These second messengers are involved in PKC and NF-kB activation and calcium mobilization (step 16).

15084594Pubmed2004T cell receptor signaling: beyond complex complexesHuang, YWange, RLJ Biol Chem 279:28827-30inferred by electronic annotationIEAGOIEA