BioPAX pathway converted from "PD-1 signaling" in the Reactome database.PD-1 signalingPD-1 signalingThis 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>PD-1 binds B7DC and B7H1PD-1 binds B7DC and B7H1This 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: 97378651plasma membraneGO0005886UniProt:Q02242Pdcd1Reactomehttp://www.reactome.orgMus musculusNCBI Taxonomy10090UniProtQ02242Chain Coordinates21EQUAL288EQUALConverted from EntitySet in ReactomeReactome DB_ID: 97378751B7-DC,B7-H1 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPdcd1lg2 [plasma membrane]Cd274 [plasma membrane]UniProtQ9WUL5UniProtQ9EP73Reactome DB_ID: 97378771PDCD1:B7-DC,B7-H1 [plasma membrane]PDCD1:B7-DC,B7-H1Reactome DB_ID: 9737865121EQUAL288EQUALConverted from EntitySet in ReactomeReactome DB_ID: 97378751Reactome Database ID Release 759737877Database 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=9737877ReactomeR-MMU-3888001Reactome 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-388800.1Reactome Database ID Release 759737881Database 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=9737881ReactomeR-MMU-3888281Reactome 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-388828.1The Programmed cell death protein 1 (PD-1) is functionally similar to CTLA4 and exerts an inhibitory signal on T cell activation. PD-1 binds the ligands B7H1 and B7DC but with different affinities. Interaction of PD-1/B7DC exhibited a 2-6-fold higher affinity and had different association/dissociation kinetics compared with the interaction of PD-1/B7H1.12893276Pubmed2003Differential binding properties of B7-H1 and B7-DC to programmed death-1Youngnak, PKozono, YKozono, HIwai, HOtsuki, NJin, HOmura, KYagita, HPardoll, DMChen, LAzuma, MBiochem Biophys Res Commun 307:672-7inferred by electronic annotationIEAGOIEAINHIBITIONReactome Database ID Release 759737882Database 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=9737882Reactome DB_ID: 9737879PDCD1:PDCD1 inhibitors [plasma membrane]PDCD1:PDCD1 inhibitorsConverted from EntitySet in ReactomeReactome DB_ID: 96794061extracellular regionGO0005576PDCD1 inhibitors [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitycemiplimab [extracellular region]camrelizumab [extracellular region]nivolumab [extracellular region]IUPHAR10090IUPHAR9758IUPHAR7335Reactome DB_ID: 9737865121EQUAL288EQUALReactome Database ID Release 759737879Database 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=9737879ReactomeR-MMU-96794201Reactome 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-9679420.1PDCD1 binds PDCD1 inhibitorsPDCD1 binds PDCD1 inhibitorsThis 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 ReactomeReactome DB_ID: 96794061Reactome DB_ID: 9737865121EQUAL288EQUALReactome DB_ID: 97378791Reactome Database ID Release 759816958Database 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=9816958ReactomeR-MMU-96794211Reactome 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-9679421.1Programmed cell death protein 1 (PDCD1, PD-1) is an immune checkpoint protein that guards against autoimmunity. It is a cell-surface protein expressed on T cells and pro-B cells. PDCD1 inhibitors are a group of checkpoint inhibitor drugs that block the activity of PDCD1 present on the surface of these cells. They are mainly used in the treatment of various cancers.<br><br>Cemiplimab (Libtayo, REGN-2810) is the first FDA approval of a drug specifically for the treatment of advanced cutaneous squamous cell carcinoma (CSCC) (Burova et al. 2017, Migden et al. 2018). Nivolumab (Opdivo) is a fully human IgG4 antibody targeting the immune checkpoint programmed death receptor 1 (PD1) (Tan et al. 2017) indicated for many cancers (Yaghoubi et al. 2019). Camrelizumab (SHR-1210) is a fully human anti-programmed cell death 1 (PD1) monoclonal antibody being developed as an immuno-oncology therapeutic (Markham & Keam 2019).<br><br>Clinical efficacy of camrelizumab plus thymosin in patients with COVID-19 is evaluated in clinical trial NCT04268537.31313098Pubmed2019Camrelizumab: First Global ApprovalMarkham, AnthonyKeam, Susan JDrugs 79:1355-136121154117Pubmed2010Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancerKline, JustinGajewski, Thomas FCurr Opin Investig Drugs 11:1354-928165004Pubmed2017An unexpected N-terminal loop in PD-1 dominates binding by nivolumabTan, ShuguangZhang, HaoChai, YanSong, HaoTong, ZhouWang, QihuiQi, JianxunWong, GaryZhu, XiaodongLiu, William JGao, ShanWang, ZhongfuShi, YiYang, FuquanGao, George FYan, JinghuaNat Commun 8:1436930522017Pubmed2019PD-1/ PD-L1 blockade as a novel treatment for colorectal cancerYaghoubi, NedaSoltani, ArashGhazvini, KiarashHassanian, Seyed MahdiHashemy, Seyed IsaacBiomed. Pharmacother. 110:312-31828265006Pubmed2017Characterization of the Anti-PD-1 Antibody REGN2810 and Its Antitumor Activity in Human <i>PD-1</i> Knock-In MiceBurova, ElenaHermann, AynurWaite, JanellePotocky, TerraLai, VenusHong, SeongwonLiu, MattAllbritton, OmairaWoodruff, AmyWu, QiD'Orvilliers, AmandaGarnova, ElenaRafique, AshiquePoueymirou, WilliamMartin, JoelHuang, TammySkokos, DimitrisKantrowitz, JoelPopke, JonMohrs, MarkusMacDonald, DouglasIoffe, EllaOlson, WilliamLowy, IsraelMurphy, AndrewThurston, GavinMol. Cancer Ther. 16:861-87029863979Pubmed2018PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell CarcinomaMigden, Michael RRischin, DannySchmults, Chrysalyne DGuminski, AlexanderHauschild, AxelLewis, Karl DChung, Christine HHernandez-Aya, LeonelLim, Annette MChang, Anne Lynn SRabinowits, GuilhermeThai, Alesha ADunn, Lara AHughes, Brett G MKhushalani, Nikhil IModi, BadriSchadendorf, DirkGao, BoSeebach, FrankLi, SiyuLi, JingjinMathias, MelissaBooth, JocelynMohan, KosalaiStankevich, ElizabethBabiker, Hani MBrana, IreneGil-Martin, MartaHomsi, JadeJohnson, Melissa LMoreno, VíctorNiu, JiaxinOwonikoko, Taofeek KPapadopoulos, Kyriakos PYancopoulos, George DLowy, IsraelFury, Matthew GN. Engl. J. Med. 379:341-35123302904Pubmed2013Beyond the standard of care: a review of novel immunotherapy trials for the treatment of lung cancerHall, Richard DGray, Jhanelle EChiappori, Alberto ACancer Control 20:22-31inferred by electronic annotationIEAGOIEA2.7.10Phosphorylation of PD-1Phosphorylation of PD-1This 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: 97378771Converted from EntitySet in ReactomeReactome DB_ID: 97380921cytosolGO0005829LCK, CSK [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityLck [cytosol]Csk [cytosol]UniProtP06240UniProtP41241Reactome DB_ID: 1135922ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 97380941p-Y223,248-PDCD1:B7-DC,B7-H1 [plasma membrane]p-Y223,248-PDCD1:B7-DC,B7-H1Reactome DB_ID: 97380901O4'-phospho-L-tyrosine at 223 (in Homo sapiens)223EQUALO4'-phospho-L-tyrosine [MOD:00048]O4'-phospho-L-tyrosine at 248 (in Homo sapiens)248EQUAL21EQUAL288EQUALConverted from EntitySet in ReactomeReactome DB_ID: 97378751Converted from EntitySet in ReactomeReactome DB_ID: 97380921Reactome Database ID Release 759738094Database 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=9738094ReactomeR-MMU-3897461Reactome 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-389746.1Reactome DB_ID: 293702ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 9738092GO0004713GO molecular functionReactome Database ID Release 759738104Database 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=9738104Reactome Database ID Release 759738106Database 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=9738106ReactomeR-MMU-3897621Reactome 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-389762.1The cytoplasmic domain of PD-1 has two tyrosine motifs, ITIM and ITSM. On engagement with B7 ligands B7DC and B7H1, PD-1 is phosphorylated on tyrosine residues 223 and 248 within these motifs. Kinases Lck and Csk also bind to these motifs and these kinases may be involved in the phosphorylation of PD-1.12947224Pubmed2003Cytotoxic T-lymphocyte antigen-4 and programmed death-1 function as negative regulators of lymphocyte activationCarter, LLCarreno, BMImmunol Res 28:49-5918173375Pubmed2008PD-1 and its ligands in tolerance and immunityKeir, MEButte, MJFreeman, GJSharpe, AHAnnu Rev Immunol 26:677-70418759926Pubmed2008Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathwaysFife, BTBluestone, JeffreyImmunol Rev 224:166-82inferred by electronic annotationIEAGOIEAInteraction of SHP-1 or SHP-2 with phospho PD-1Interaction of SHP-1 or SHP-2 with phospho PD-1This 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: 97380941Converted from EntitySet in ReactomeReactome DB_ID: 97380961PTPN6,PTPN11 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPtpn6 [cytosol]Ptpn11 [cytosol]UniProtP29351UniProtP35235Reactome DB_ID: 97380981PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1 [plasma membrane]PTPN6,PTPN11:p-Y223,248-PDCD1:B7-DC,B7-H1Reactome DB_ID: 97380941Converted from EntitySet in ReactomeReactome DB_ID: 97380961Reactome Database ID Release 759738098Database 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=9738098ReactomeR-MMU-3897491Reactome 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-389749.1Reactome Database ID Release 759738103Database 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=9738103ReactomeR-MMU-3897591Reactome 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-389759.1Once phosphorylated, SH2-domain containing tyrosine phosphatases SHP-1 and SHP-2 bind to the ITIM and ITSM motifs of PD-1. The association between SHP-1 and PD-1 appears to be weaker than the interaction of PD-1 with SHP-2.inferred by electronic annotationIEAGOIEA3.1.3.48Dephosphorylation of CD3-zeta by PD-1 bound phosphatasesDephosphorylation of CD3-zeta by PD-1 bound phosphatasesThis 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: 97278471Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4 [plasma membrane]Antigen-bearing MHC Class II: TCR with phosphorylated ITAMs:CD4Reactome DB_ID: 97277811UniProt:P06332Cd4UniProtP0633226EQUAL458EQUALReactome DB_ID: 97278151MHC Class II bearing antigen peptide [plasma membrane]MHC Class II bearing antigen peptideReactome DB_ID: 97278131MHC class II alpha/beta dimer [plasma membrane]MHC class II alpha/beta dimerConverted from EntitySet in ReactomeReactome DB_ID: 97278111HLA II beta chain [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityH2-Eb1 [plasma membrane]H2-Eb2 [plasma membrane]H2-Ab1 [plasma membrane]UniProtP04230UniProtQ3UUV9UniProtP01921Converted from EntitySet in ReactomeReactome DB_ID: 97277931HLA II alpha chain [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityH2-Aa [plasma membrane]H2-Ea [plasma membrane]UniProtP01910UniProtP01904Reactome Database ID Release 759727813Database 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=9727813ReactomeR-MMU-22131891Reactome 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 DB_ID: 1735481Antigen [plasma membrane]AntigenReactome Database ID Release 759727815Database 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=9727815ReactomeR-MMU-2034631Reactome 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-203463.1Reactome DB_ID: 97278451T-cell receptor complex with phosphorylated ITAMs [plasma membrane]T-cell receptor complex with phosphorylated ITAMsReactome DB_ID: 97263901T-cell receptor [plasma membrane]T-cell receptorConverted from EntitySet in ReactomeReactome DB_ID: 97263881TCR chain beta [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTrbc2 [plasma membrane]Trbc1 [plasma membrane]Trbv16 [plasma membrane]UniProtA0A075B5J4UniProtA0A075B5J3UniProtA0A0B4J1H3Converted from EntitySet in ReactomeReactome DB_ID: 97263721TCR chain alpha [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTrav16 [plasma membrane]Trac [plasma membrane]Trav19 [plasma membrane]UniProtA0A075B653UniProtA0A075B662UniProtA0A0B4J1K4Reactome Database ID Release 759726390Database 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=9726390ReactomeR-MMU-1981831Reactome 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-198183.1Reactome DB_ID: 97278331CD3 epsilon: CD3 gamma with phosphorylated ITAM [plasma membrane]CD3 epsilon: CD3 gamma with phosphorylated ITAMReactome DB_ID: 97278311UniProt:P11942Cd3gUniProtP11942O4'-phospho-L-tyrosine at 160 (in Homo sapiens)160EQUALO4'-phospho-L-tyrosine at 171 (in Homo sapiens)171EQUAL23EQUAL182EQUALReactome DB_ID: 97278211UniProt:P22646Cd3eUniProtP22646O4'-phospho-L-tyrosine at 188 (in Homo sapiens)188EQUALO4'-phospho-L-tyrosine at 199 (in Homo sapiens)199EQUAL23EQUAL207EQUALReactome Database ID Release 759727833Database 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=9727833ReactomeR-MMU-2021671Reactome 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 DB_ID: 97278431p-6Y-CD247 dimer [plasma membrane]p-6Y-CD247 dimerReactome DB_ID: 97278412UniProt:P24161Cd247UniProtP24161O4'-phospho-L-tyrosine at 72 (in Homo sapiens)72EQUALO4'-phospho-L-tyrosine at 83 (in Homo sapiens)83EQUALO4'-phospho-L-tyrosine at 111 (in Homo sapiens)111EQUALO4'-phospho-L-tyrosine at 123 (in Homo sapiens)123EQUALO4'-phospho-L-tyrosine at 142 (in Homo sapiens)142EQUALO4'-phospho-L-tyrosine at 153 (in Homo sapiens)153EQUAL22EQUAL164EQUALReactome Database ID Release 759727843Database 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=9727843ReactomeR-MMU-2023031Reactome 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-202303.1Reactome DB_ID: 97278271CD3 epsilon: CD3 delta with phosphorylated ITAMs [plasma membrane]CD3 epsilon: CD3 delta with phosphorylated ITAMsReactome DB_ID: 97278251UniProt:P04235Cd3dUniProtP04235O4'-phospho-L-tyrosine at 149 (in Homo sapiens)149EQUALO4'-phospho-L-tyrosine at 160 (in Homo sapiens)160EQUAL22EQUAL171EQUALReactome DB_ID: 97278211O4'-phospho-L-tyrosine at 188 (in Homo sapiens)188EQUALO4'-phospho-L-tyrosine at 199 (in Homo sapiens)199EQUAL23EQUAL207EQUALReactome Database ID Release 759727827Database 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=9727827ReactomeR-MMU-2023361Reactome 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-202336.1Reactome Database ID Release 759727845Database 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=9727845ReactomeR-MMU-2034931Reactome 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-203493.1Reactome DB_ID: 97277771UniProt:P06240 LckLckLckLsk-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 association with the plasma membrane and could be mediated by ZDHHC2.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.O4'-phospho-L-tyrosine at 394 (in Homo sapiens)394EQUAL1EQUAL509EQUALReactome Database ID Release 759727847Database 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=9727847ReactomeR-MMU-2034941Reactome 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-203494.1Reactome DB_ID: 97380861Antigen-bearing MHC Class II: TCR with dephosphorylated CD3 zeta chain:CD4 [plasma membrane]Antigen-bearing MHC Class II: TCR with dephosphorylated CD3 zeta chain:CD4Reactome DB_ID: 9727781126EQUAL458EQUALReactome DB_ID: 97380841T-cell receptor complex with dephosphorylated CD3 zeta chain [plasma membrane]T-cell receptor complex with dephosphorylated CD3 zeta chainReactome DB_ID: 97263901Reactome DB_ID: 9726410222EQUAL164EQUALReactome DB_ID: 97278331Reactome DB_ID: 97278271Reactome Database ID Release 759738084Database 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=9738084ReactomeR-MMU-3903411Reactome 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-390341.1Reactome DB_ID: 97278151Reactome DB_ID: 97277771O4'-phospho-L-tyrosine at 394 (in Homo sapiens)394EQUAL1EQUAL509EQUALReactome Database ID Release 759738086Database 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=9738086ReactomeR-MMU-3903391Reactome 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-390339.1Reactome DB_ID: 11129412diphosphoric acid [ChEBI:29888]diphosphoric acidChEBI29888PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9738098GO0004725GO molecular functionReactome Database ID Release 759738099Database 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=9738099Reactome Database ID Release 759738101Database 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=9738101ReactomeR-MMU-3897581Reactome 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-389758.1PD-1 delivers inhibitory signals and downregulates antigen receptor signaling through direct dephosphorylation of signaling intermediates. The phosphatases SHP-1 and SHP-2 dephosphorylate CD3 zeta and inhibit the phosphorylation of ZAP-70 and PKC theta.15358536Pubmed2004PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCthetaSheppard, KAFitz, LJLee, JMBenander, CGeorge, JAWooters, JQiu, YJussif, JMCarter, LLWood, CRChaudhary, DFEBS Lett 574:37-41inferred by electronic annotationIEAGOIEAReactome Database ID Release 759818982Database 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=9818982ReactomeR-MMU-3899481Reactome 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-389948.1The Programmed cell death protein 1 (PD-1) is one of the negative regulators of TCR signaling. PD-1 may exert its effects on cell differentiation and survival directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. PD-1 ligation inhibits the induction of the cell survival factor Bcl-xL and the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes. PD-1 exerts its inhibitory effects by bringing phosphatases SHP-1 and SHP-2 into the immune synapse, leading to dephosphorylation of CD3-zeta chain, PI3K and AKT.inferred by electronic annotationIEAGOIEA