BioPAX pathway converted from "p-RasGRP1,3:DAG cause RAS to exchange GDP for GTP" in the Reactome database.LEFT-TO-RIGHTActivation of RAS by RasGRP1 and RasGRP3p-RasGRP1,3:DAG cause RAS to exchange GDP for GTPRasGRP1 (Roose et al. 2007) and RasGRP3 (Ohba et al. 2000, Yamashita et al. 2000, Rebhun et al. 2000, Lorenzo et al. 2001) catalyze the exchange of GDP for GTP bound by RAS.Authored: May, B, 2011-01-03Reviewed: Wienands, J, 2012-02-11Edited: May, B, 2010-12-18GTPGuanosine 5'-triphosphateReactome DB_ID: 29438cytosolGENE ONTOLOGYGO:0005829GTP [ChEBI:15996]GTPGuanosine 5'-triphosphateChEBICHEBI:15996Reactome Database ID Release 7029438Database 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=29438ReactomeR-ALL-294383Reactome 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-ALL-29438.3Reactomehttp://www.reactome.orgp21 RAS:GDPReactome DB_ID: 109796plasma membraneGENE ONTOLOGYGO:0005886Converted from EntitySet in Reactomemature p21 RASReactome DB_ID: 9649715Ki-RasS-Farn-Me-PalmS KRAS4Ap21A (K-Ras 2A)Transforming protein p21AK-Ras 2Ac-K-rasReactome DB_ID: 9647915UniProt:P01116-1 KRASKRASKRAS2RASK2FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838). Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner (PubMed:24623306).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP). Interaction with SOS1 promotes exchange of bound GDP by GTP.SUBUNIT Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane (PubMed:23698361). Interacts with SOS1 (PubMed:22431598).PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.DISEASE Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.DISEASE KRAS mutations are involved in cancer development.SIMILARITY Belongs to the small GTPase superfamily. Ras family.Homo sapiensNCBI Taxonomy9606UniProt IsoformP01116-1186EQUALS-farnesyl-L-cysteine methyl esterMODMOD:01116179EQUALS-palmitoyl-L-cysteineMODMOD:001151EQUAL186EQUALReactome Database ID Release 709647915Database 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=9647915ReactomeR-HSA-96479151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647915.1p21/N-RasS-Farn-Me PalmS NRASTransforming protein N-RasReactome DB_ID: 9647910UniProt:P01111 NRASNRASHRAS1FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).SUBUNIT Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (active GTP-bound form) with RASSF7 (PubMed:21278800).PTM Palmitoylated by the ZDHHC9-GOLGA7 complex (PubMed:16000296). Depalmitoylated by ABHD17A, ABHD17B and ABHD17C (PubMed:26701913). A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi (PubMed:16000296, PubMed:15705808, PubMed:2661017, PubMed:26701913).PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.PTM Phosphorylation at Ser-89 by STK19 enhances NRAS-association with its downstream effectors.MISCELLANEOUS Mutations which change AA 12, 13 or 61 activate the potential of Ras to transform cultured cells and are implicated in a variety of human tumors.SIMILARITY Belongs to the small GTPase superfamily. Ras family.UniProtP01111186EQUAL181EQUAL1EQUAL186EQUALReactome Database ID Release 709647910Database 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=9647910ReactomeR-HSA-96479101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647910.1RasS-Farn-Me-2xPalmS HRASp21/H-RAS-1 Transforming protein p21/H-Ras-1c-H-rasReactome DB_ID: 9647912UniProt:P01112 HRASHRASHRAS1FUNCTION Involved in the activation of Ras protein signal transduction (PubMed:22821884). Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:12740440, PubMed:14500341, PubMed:9020151).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP).SUBUNIT In its GTP-bound form interacts with PLCE1 (PubMed:11022048). Interacts with TBC1D10C (PubMed:17230191). Interacts with RGL3 (By similarity). Interacts with HSPD1 (By similarity). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14 (By similarity). Interacts (active GTP-bound form) with RGS14 (via RBD 1 domain) (By similarity). Forms a signaling complex with RASGRP1 and DGKZ (PubMed:11257115). Interacts with RASSF5 (PubMed:18596699). Interacts with PDE6D (PubMed:11980706). Interacts with IKZF3 (PubMed:10369681). Interacts with RACK1 (PubMed:14500341). Interacts with PIK3CG; the interaction is required for membrane recruitment and beta-gamma G protein dimer-dependent activation of the PI3K gamma complex PIK3CG:PIK3R6 (By similarity). Interacts with RAPGEF2 (PubMed:10608844, PubMed:11598133).TISSUE SPECIFICITY Widely expressed.PTM Palmitoylated by the ZDHHC9-GOLGA7 complex. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi.PTM S-nitrosylated; critical for redox regulation. Important for stimulating guanine nucleotide exchange. No structural perturbation on nitrosylation.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation.PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.DISEASE Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors.SIMILARITY Belongs to the small GTPase superfamily. Ras family.UniProtP01112186EQUAL181EQUAL184EQUAL1EQUAL186EQUALReactome Database ID Release 709647912Database 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=9647912ReactomeR-HSA-96479121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647912.1Ki-RasS-Farn-Me KRAS4Bp21A (K-Ras 2A)Transforming protein p21AK-Ras 2Ac-K-rasReactome DB_ID: 9647815UniProt:P01116-2 KRASKRASKRAS2RASK2FUNCTION Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838). Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner (PubMed:24623306).ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP). Interaction with SOS1 promotes exchange of bound GDP by GTP.SUBUNIT Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14 (By similarity). Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane (PubMed:23698361). Interacts with SOS1 (PubMed:22431598).PTM Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).PTM Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.DISEASE Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.DISEASE KRAS mutations are involved in cancer development.SIMILARITY Belongs to the small GTPase superfamily. Ras family.UniProt IsoformP01116-2186EQUAL1EQUAL186EQUALReactome Database ID Release 709647815Database 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=9647815ReactomeR-HSA-96478151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9647815.1Reactome Database ID Release 709649715Database 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=9649715ReactomeR-HSA-96497151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9649715.11GDPGuanosine 5'-diphosphateGuanosine diphosphateReactome DB_ID: 29420GDP [ChEBI:17552]GDPGuanosine 5'-diphosphateGuanosine diphosphateChEBICHEBI:17552Reactome Database ID Release 7029420Database 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=29420ReactomeR-ALL-294202Reactome 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-ALL-29420.21Reactome Database ID Release 70109796Database 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=109796ReactomeR-HSA-1097962Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109796.2p21 RAS:GTPReactome DB_ID: 10978311Reactome Database ID Release 70109783Database 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=109783ReactomeR-HSA-1097832Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109783.2ACTIVATIONactiveUnit: #Protein6p-RASGRP1,3:DAGPhosphorylated RasGRP1,3:DiacylglycerolPhosphorylated RasGRP3:Diacylglycerol and phosphorylated RasGRP1:DiacylglycerolReactome DB_ID: 1168369Converted from EntitySet in Reactomep-RASGRP1,3Phosphorylated RasGRP1 and phosphorylated RasGRP3Reactome DB_ID: 1169483RasGRPp-T184-RASGRP1RASGRP1 phosphorylated at threonine-184CalDAG-GEFIIRAS guanyl-releasing protein 1GRP1_HUMANReactome DB_ID: 1169559UniProt:O95267 RASGRP1RASGRP1RASGRPFUNCTION Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP (PubMed:15899849, PubMed:23908768). Activates the Erk/MAP kinase cascade (PubMed:15899849). Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors to Ras (PubMed:10807788, PubMed:12839994). Regulates NK cell cytotoxicity and ITAM-dependent cytokine production by activation of Ras-mediated ERK and JNK pathways (PubMed:19933860). Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses (By similarity). May also function in differentiation of other cell types (PubMed:12845332).ACTIVITY REGULATION Autoinhibited. Activated by diacylglycerol and calcium binding, which induces a conformational change releasing the autoinhibitory state (PubMed:23908768). Regulated by DGKA (PubMed:11919165). Regulated by DGKZ (PubMed:11257115). Regulated by PLC gamma and F-actin polymerization (PubMed:12839994).SUBUNIT Homodimer (PubMed:23908768). Forms a signaling complex with DGKZ and HRAS (PubMed:11257115). Interacts with F-actin (PubMed:12839994). Interacts with SKAP1 (PubMed:17658605).TISSUE SPECIFICITY Expressed in brain with higher expression in cerebellum, cerebral cortex and amygdala. Expressed in the hematopoietic system. Expressed in T-cells (at protein level). Expressed in NK cells (at protein level) (PubMed:19933860).DEVELOPMENTAL STAGE Expressed in fetal brain and kidney.DOMAIN The phorbol-ester/DAG-type zinc finger is the principal mediator of the targeting to membranes and is required for functional activation through DAG-binding.DOMAIN Two EF-hand domains are present. However, only EF-hand 1 (and not EF-hand 2) binds calcium.SIMILARITY Belongs to the RASGRP family.UniProtO95267184EQUALO-phospho-L-threonineMODMOD:000471EQUAL797EQUALReactome Database ID Release 701169559Database 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=1169559ReactomeR-HSA-11695591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169559.1RASGRP3p-T133-RASGRP3Ras guanyl-releasing protein 3 phosphorylated at Threonine-133GRP3_HUMANCalDAG-GEFIIIReactome DB_ID: 1168362UniProt:Q8IV61 RASGRP3RASGRP3GRP3KIAA0846FUNCTION Guanine nucleotide exchange factor (GEF) for Ras and Rap1.SIMILARITY Belongs to the RASGRP family.UniProtQ8IV61133EQUAL1EQUAL690EQUALReactome Database ID Release 701168362Database 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=1168362ReactomeR-HSA-11683621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1168362.1Reactome Database ID Release 701169483Database 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=1169483ReactomeR-HSA-11694831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1169483.11DAG1,2-Diacylglycerol1,2-diacyl-sn-glycerolReactome DB_ID: 1145191,2-diacyl-sn-glycerol [ChEBI:17815]1,2-diacyl-sn-glycerolChEBICHEBI:17815Reactome Database ID Release 70114519Database 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=114519ReactomeR-ALL-1145194Reactome 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-ALL-114519.41Reactome Database ID Release 701168369Database 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=1168369ReactomeR-HSA-11683691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1168369.1GENE ONTOLOGYGO:0005085gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 701168627Database 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=1168627Reactome Database ID Release 701168636Database 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=1168636ReactomeR-HSA-11686362Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1168636.210777492Pubmed2000Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3Ohba, YMochizuki, NYamashita, SChan, AMSchrader, JWHattori, SNagashima, KMatsuda, MJ Biol Chem 275:20020-610934204Pubmed2000Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interactionRebhun, JFCastro, AFQuilliam, LAJ Biol Chem 275:34901-810835426Pubmed2000CalDAG-GEFIII activation of Ras, R-ras, and Rap1Yamashita, SMochizuki, NOhba, YTobiume, MOkada, YSawa, HNagashima, KMatsuda, MJ Biol Chem 275:25488-9317283063Pubmed2007Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytesRoose, JPMollenauer, MHo, MKurosaki, TWeiss, AMol Cell Biol 27:2732-4511221888Pubmed2001Phorbol esters modulate the Ras exchange factor RasGRP3Lorenzo, PSKung, JWBottorff, DAGarfield, SHStone, JCBlumberg, PMCancer Res 61:943-9