BioPAX pathway converted from "Integrin signaling" in the Reactome database.Integrin signalingIntegrin 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>Activation of Rap1 by cytosolic GEFsActivation of Rap1 by cytosolic GEFsThis 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: 294381cytosolGO0005829GTP [ChEBI:15996]GTPGuanosine 5'-triphosphateReactomehttp://www.reactome.orgChEBI15996Reactome DB_ID: 106571791plasma membraneGO0005886RAP1:GDP [plasma membrane]RAP1:GDPConverted from EntitySet in ReactomeReactome DB_ID: 106571751RAP1 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityrapA [plasma membrane]rapC [plasma membrane]RAP1A [plasma membrane]rapB [plasma membrane]Dictyostelium discoideumNCBI Taxonomy44689UniProtP18613UniProtQ55BW0UniProtQ54BC3UniProtQ86L51Reactome DB_ID: 294201GDP [ChEBI:17552]GDPGuanosine 5'-diphosphateGuanosine diphosphateChEBI17552Reactome Database ID Release 7510657179Database 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=10657179ReactomeR-DDI-3540741Reactome 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-DDI-354074.1Reactome DB_ID: 106571771RAP1:GTP [plasma membrane]RAP1:GTPConverted from EntitySet in ReactomeReactome DB_ID: 106571751Reactome DB_ID: 294381Reactome Database ID Release 7510657177Database 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=10657177ReactomeR-DDI-3541261Reactome 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-DDI-354126.1Reactome DB_ID: 294201PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 10657255CalDAG-GEFs:DAG:Ca2+ [plasma membrane]CalDAG-GEFs:DAG:Ca2+Converted from EntitySet in ReactomeReactome DB_ID: 106572531CalDAG-GEFs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitygefW [cytosol]gefG [cytosol]gefD [cytosol]gefK [cytosol]RASGRP1 [cytosol]gefM [cytosol]gefE [cytosol]gefD [cytosol]gefW [cytosol]RASGRP2 [cytosol]gefK [cytosol]RASGRP2 [cytosol]gefN [cytosol]gefM [cytosol]gefO [cytosol]gefG [cytosol]gefQ [cytosol]gefE [cytosol]gflB [cytosol]gefC [cytosol]RASGRP1 [cytosol]gefL [cytosol]gefY [cytosol]gefY [cytosol]gefQ [cytosol]gflB [cytosol]gefC [cytosol]gefB [cytosol]gefB [cytosol]gefL [cytosol]gefS [cytosol]gefN [cytosol]gefS [cytosol]gefO [cytosol]UniProtQ55GH9UniProtQ8ST25UniProtQ8IS19UniProtQ54FF3UniProtQ54XL4UniProtQ8SSQ3UniProtQ8IS18UniProtQ54WL2UniProtQ8IS12UniProtQ8IS11UniProtQ86G47UniProtQ54L90UniProtQ8IS20UniProtB0M0P8UniProtQ552M5UniProtQ8IS21UniProtQ8SSW7Reactome DB_ID: 740161calcium(2+) [ChEBI:29108]calcium(2+)ChEBI29108Reactome DB_ID: 11451911,2-diacyl-sn-glycerol [ChEBI:17815]1,2-diacyl-sn-glycerolChEBI17815Reactome Database ID Release 7510657255Database 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=10657255ReactomeR-DDI-3928411Reactome 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-DDI-392841.1GO0005085GO molecular functionReactome Database ID Release 7510657256Database 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=10657256Reactome Database ID Release 7510657258Database 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=10657258ReactomeR-DDI-3541731Reactome 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-DDI-354173.1Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP.15469846Pubmed2004RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesionLafuente, EMvan Puijenbroek, AAKrause, MCarman, CVFreeman, GJBerezovskaya, AConstantine, ESpringer, TAGertler, FBBoussiotis, VADev Cell 7:585-9516757337Pubmed2006Rap1 regulation of RIAM and cell adhesionLafuente, EBoussiotis, VAMethods Enzymol 407:345-5815334074Pubmed2004CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formationCrittenden, JRBergmeier, WZhang, YPiffath, CLLiang, YWagner, DDHousman, DEGraybiel, AMNat Med 10:982-616076873Pubmed2005Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functionsStork, PJDillon, TJBlood 106:2952-6112585966Pubmed2003Bidirectional integrin alphaIIbbeta3 signalling regulating platelet adhesion under flow: contribution of protein kinase CGiuliano, SNesbitt, WSRooney, MJackson, SPBiochem J 372:163-72inferred by electronic annotationIEAGOIEAActivation of Rap1 by membrane-associated GEFsActivation of Rap1 by membrane-associated GEFsThis 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: 294381Reactome DB_ID: 106571791Reactome DB_ID: 106571771Reactome DB_ID: 294201PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 10658403Rap1 cAMP-GEFs [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitygefH [plasma membrane]gefI [plasma membrane]gbpD [plasma membrane]gefV [plasma membrane]gefR [plasma membrane]gefF [plasma membrane]gefJ [plasma membrane]gefA [plasma membrane]gefP [plasma membrane]RAPGEF3 [plasma membrane]gefP [plasma membrane]UniProtQ8IS16UniProtQ8IS15UniProtQ54S40UniProtQ55FD8UniProtQ8SSQ0UniProtQ54C94UniProtQ8IS14UniProtQ54PQ4UniProtQ54TK8UniProtQ54H95Reactome Database ID Release 7510662598Database 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=10662598Reactome Database ID Release 7510662600Database 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=10662600ReactomeR-DDI-9392651Reactome 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-DDI-939265.1Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP.inferred by electronic annotationIEAGOIEAReactome Database ID Release 7510697575Database 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=10697575ReactomeR-DDI-3541921Reactome 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-DDI-354192.1Integrins are a major family of cell surface receptors that modulate cell adhesion, migration, proliferation and survival through interaction with the extracellular matrix (ECM) and the actin cytoskeleton. Integrins are type 1 transmembrane proteins that exist at the cell surface as heterodimers of alpha and beta subunits, of which there are 18 and 8 different isoforms, respectively, in human cells. In addition to their mechanical role in mediating contact between the ECM and the cytoskeleton, integrins also modulate intracellular signaling pathways governing cytoskeletal rearrangements and pro-survival and mitogenic signaling (reviewed in Hehlgans et al, 2007; Harburger and Calderwood, 2009; Ata and Antonescu, 2017). <br>In this pathway, we describe signaling through integrin alphaIIb beta3 as a representative example.<br> At the sites of vascular injury bioactive molecules such as thrombin, ADP, collagen, fibrinogen and thrombospondin are generated, secreted or exposed. These stimuli activate platelets, converting the major platelet integrin alphaIIbbeta3 from a resting state to an active conformation, in a process termed integrin priming or 'inside-out signalling'. Integrin activation refers to the change required to enhance ligand-binding activity. The activated alphaIIbbeta3 interacts with the fibrinogen and links platelets together in an aggregate to form a platelet plug. AlphaIIbbeta3 bound to fibrin generates more intracellular signals (outside-in signalling), causing further platelet activation and platelet-plug retraction. <br>In the resting state the alpha and beta tails are close together. This interaction keeps the membrane proximal regions in a bent conformation that maintains alphaIIbbeta3 in a low affinity state. <br>Integrin alphaIIbbeta3 is released from its inactive state by interaction with the protein talin. Talin interacts with the beta3 cytoplasmic domain and disrupts the salt bridge between the alpha and beta chains. This separation in the cytoplasmic regions triggers the conformational change in the extracellular domain that increases its affinity to fibrinogen. <br>Much of talin exists in an inactive cytosolic pool, and the Rap1 interacting adaptor molecule (RIAM) is implicated in talin activation and translocation to beta3 integrin cytoplasmic domain.<br>16102042Pubmed2005GPVI and integrin alphaIIb beta3 signaling in plateletsWatson, SPAuger, JMMcCarty, OJPearce, ACJ Thromb Haemost 3:1752-6217624957Pubmed2007Platelet integrins and immunoreceptorsKasirer-Friede, AKahn, MLShattil, Sanford JImmunol Rev 218:247-6410508650Pubmed1999Integrin alpha(IIb)beta(3) signaling in platelet adhesion and aggregationParise, LVCurr Opin Cell Biol 11:597-60119118207Pubmed2009Integrin signalling at a glanceHarburger, David SCalderwood, David AJ. Cell. Sci. 122:159-6315205259Pubmed2004Integrins: dynamic scaffolds for adhesion and signaling in plateletsShattil, Sanford JNewman, PJBlood 104:1606-1514754902Pubmed2004Integrin activationCalderwood, DAJ Cell Sci 117:657-6610605720Pubmed1999Signaling through platelet integrin alpha IIb beta 3: inside-out, outside-in, and sidewaysShattil, Sanford JThromb Haemost 82:318-2517084981Pubmed2007Signalling via integrins: implications for cell survival and anticancer strategiesHehlgans, SHaase, MCordes, NBiochim Biophys Acta 1775:163-8028106780Pubmed2017Integrins and Cell Metabolism: An Intimate Relationship Impacting CancerAta, RehmanAntonescu, Costin NInt J Mol Sci 18:inferred by electronic annotationIEAGOIEA