BioPAX pathway converted from "G alpha (q) signalling events" in the Reactome database.

G alpha (q) signalling events

This event has been computationally inferred from an event that has been demonstrated in another species.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.<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>

Liganded Gq/11-activating GPCRs act as GEFs for Gq/11

Reactome DB_ID: 29438

cytosolGO0005829

GTP [ChEBI:15996]

GTP

Guanosine 5'-triphosphate

Reactomehttp://www.reactome.orgChEBI15996

Reactome DB_ID: 9847953

plasma membraneGO0005886Ligand:GPCR complexes that activate Gq/11:Heterotrimeric G-protein Gq (inactive) [plasma membrane]

Ligand:GPCR complexes that activate Gq/11:Heterotrimeric G-protein Gq (inactive)

Reactome DB_ID: 9830154

Heterotrimeric G-protein Gq/11 (inactive) [plasma membrane]

Heterotrimeric G-protein Gq/11 (inactive)

Reactome DB_ID: 9829597

G-protein beta-gamma complex [plasma membrane]

G-protein beta-gamma complex

Converted from EntitySet in Reactome

Reactome DB_ID: 9829573

G-protein gamma subunit [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Converted from EntitySet in Reactome

Reactome DB_ID: 9829595

G-protein beta subunit [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGnb1 [cytosol]

Rattus norvegicus

NCBI Taxonomy10116UniProtP54311Reactome Database ID Release 759829597Database 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=9829597ReactomeR-RNO-167434

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-RNO-167434.1

Reactome DB_ID: 9830152

G-protein alpha (q/11):GDP [plasma membrane]

G-protein alpha (q/11):GDP

Reactome DB_ID: 114549

GDP [ChEBI:17552]

GDP

Guanosine 5'-diphosphateGuanosine diphosphate

ChEBI17552Converted from EntitySet in Reactome

Reactome DB_ID: 9830150

G-protein alpha (q/11) [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGna14 [plasma membrane]Gna11 [plasma membrane]Gnaq [plasma membrane]Gna15 [plasma membrane]

UniProtQ5EAP4UniProtQ9JID2UniProtP82471UniProtO88302Reactome Database ID Release 759830152Database 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=9830152ReactomeR-RNO-114556

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-RNO-114556.1Reactome Database ID Release 759830154Database 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=9830154ReactomeR-RNO-114557

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-RNO-114557.1Converted from EntitySet in Reactome

Reactome DB_ID: 9847951

photoreceptor disc membraneGO0097381

Ligand:GPCR complexes that activate Gq/11 [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 759847953Database 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=9847953ReactomeR-RNO-749451

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-RNO-749451.1

Reactome DB_ID: 9847955

Ligand:GPCR complexes that activate Gq/11:Heterotrimeric G-protein Gq (active) [plasma membrane]

Ligand:GPCR complexes that activate Gq/11:Heterotrimeric G-protein Gq (active)

Reactome DB_ID: 9830160

Heterotrimeric G-protein Gq (active) [plasma membrane]

Heterotrimeric G-protein Gq (active)

Reactome DB_ID: 9830158

G-protein alpha (q/11): GTP [plasma membrane]

G-protein alpha (q/11): GTP

Reactome DB_ID: 29438

Converted from EntitySet in Reactome

Reactome DB_ID: 9830150

Reactome Database ID Release 759830158Database 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=9830158ReactomeR-RNO-114534

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-RNO-114534.1

Reactome DB_ID: 9829597

Reactome Database ID Release 759830160Database 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=9830160ReactomeR-RNO-114554

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-RNO-114554.1Converted from EntitySet in Reactome

Reactome DB_ID: 9847951

Reactome Database ID Release 759847955Database 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=9847955ReactomeR-RNO-749447

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-RNO-749447.1

Reactome DB_ID: 29420

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9847959

LTC4:CyslTR1,2 [plasma membrane]

LTC4:CyslTR1,2

Reactome DB_ID: 266013

extracellular regionGO0005576

leukotriene C4 [ChEBI:16978]

leukotriene C4

ChEBI16978Converted from EntitySet in Reactome

Reactome DB_ID: 9847957

CYSLTR1,CYSLTR2 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCysltr2 [plasma membrane]Cysltr1 [plasma membrane]

UniProtQ924T9UniProtQ924T8Reactome Database ID Release 759847959Database 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=9847959ReactomeR-RNO-9664302

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-RNO-9664302.1GO0005085

GO molecular function

Reactome Database ID Release 759847960Database 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=9847960Reactome Database ID Release 759847962Database 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=9847962ReactomeR-RNO-379048

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-RNO-379048.1G alpha q protein (or Gq/11) consists of four family members (G-alpha 11, -alpha 14, -alpha 15 and -alpha q). It activates phospholipase C (PLC) (Dowal L et al, 2006). PLC hydrolyzes phosphatidylinositol (PIP2) to diacyl glycerol (DAG) and inositol triphosphate (IP3). DAG acts as a second messenger that activates protein kinase C (PKC) and IP3 can bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). Calcium flow causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity.

8664309Pubmed1996Human G(alpha q): cDNA and tissue distributionChen, BLeverette, RDSchwinn, DAKwatra, MMBiochim Biophys Acta 1281:125-83086311Pubmed1986The influence of bound GDP on the kinetics of guanine nucleotide binding to G proteinsFerguson, KMHigashijima, TSmigel, MDGilman, AGJ Biol Chem 261:7393-916754659Pubmed2006Stable association between G alpha(q) and phospholipase C beta 1 in living cellsDowal, LProvitera, PScarlata, SJ Biol Chem 281:23999-40141905813Pubmed1991G alpha 16, a G protein alpha subunit specifically expressed in hematopoietic cellsAmatruda TT, 3rdSteele, DASlepak, VZSimon, MIProc Natl Acad Sci U S A 88:5587-9110191087Pubmed1999Genomic organization of the human galpha14 and Galphaq genes and mutation analysis in chorea-acanthocytosis (CHAC)Rubio, JPLevy, ERDobson-Stone, CMonaco, APGenomics 57:84-93inferred by electronic annotationIEAGOIEA

GRK2 sequesters activated Gq

Reactome DB_ID: 9830158

Reactome DB_ID: 9829407

UniProt:P26817Grk2

UniProtP26817

Chain Coordinates

EQUAL

689

EQUAL

Reactome DB_ID: 9853244

G-protein alpha (q):GRK2 [plasma membrane]

G-protein alpha (q):GRK2

Reactome DB_ID: 9830158

Reactome DB_ID: 9829407

EQUAL

689

EQUAL

Reactome Database ID Release 759853244Database 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=9853244ReactomeR-RNO-416515

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-RNO-416515.1Reactome Database ID Release 759853246Database 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=9853246ReactomeR-RNO-416516

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-RNO-416516.1GRK2 can inhibit GPCR signaling via phosphorylation-independent sequestration of Gq/11/14 subunits utilising its RGS homology (RH) domain. GRK2 may be an effector of activated Gq, initiating signalling cascades other than the classical PLC beta signalling associated with Gq.

10727532Pubmed2000Selective regulation of Gq signaling by G protein-coupled receptor kinase 2: direct interaction of kinase N terminus with activated galphaqSallese, MMariggiò, SD'Urbano, EIacovelli, LDe Blasi, AMol. Pharmacol. 57:826-3116339447Pubmed2005Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complexTesmer, VMKawano, TShankaranarayanan, AKozasa, TTesmer, JJScience 310:1686-9018936096Pubmed2008Assembly of high order G alpha q-effector complexes with RGS proteinsShankaranarayanan, AThal, DMTesmer, VMRoman, DLNeubig, RRKozasa, TTesmer, JJJ Biol Chem 283:34923-3410567430Pubmed1999Selective regulation of Galpha(q/11) by an RGS domain in the G protein-coupled receptor kinase, GRK2Carman, CVParent, JLDay, PWPronin, ANSternweis, PMWedegaertner, PBGilman, AGBenovic, JLKozasa, TJ Biol Chem 274:34483-92inferred by electronic annotationIEAGOIEA

G alpha (q) binds to Trio family RhoGEFs

Reactome DB_ID: 9830158

Converted from EntitySet in Reactome

Reactome DB_ID: 9853127

TRIO family RhoGEFs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityArhgef25 [cytosol]Trio [cytosol]Kalrn [cytosol]

UniProtQ6P720UniProtF1M0Z1UniProtP97924

Reactome DB_ID: 9853129

G-protein alpha (q/11):Trio family RhoGEFs [plasma membrane]

G-protein alpha (q/11):Trio family RhoGEFs

Reactome DB_ID: 9830158

Converted from EntitySet in Reactome

Reactome DB_ID: 9853127

Reactome Database ID Release 759853129Database 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=9853129ReactomeR-RNO-400608

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-RNO-400608.1Reactome Database ID Release 759853131Database 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=9853131ReactomeR-RNO-400586

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-RNO-400586.1The Trio family of RhoA guanine nucleotide exchange factors (RhoGEFs) are directly activated by G alpha (q), possibly within a Gq:Trio:RhoA signalling complex, thereby linking Gq to RhoA-mediated processes such as cell migration, proliferation, and contraction. Like most other RhoGEFs, they have a tandem motif consisting of a Dbl homology (DH) and a pleckstrin homology (PH) domain. Trio and Duet have a number of other domains including an immunoglobin domains that may be involved in interacting with Rho, but the considerably smaller GEFT (p63RhoGEF) does not have any identifiable additional domains yet appears to be sufficient to mediate the activation of RhoA by G alpha (q). The structure represented by GEFT is proposed to represent the core of an ancient signal transduction pathway.

17942708Pubmed2007Trio's Rho-specific GEF domain is the missing Galpha q effector in C. elegansWilliams, SLLutz, SCharlie, NKVettel, CAilion, MCoco, CTesmer, JJJorgensen, EMWieland, TMiller, KGGenes Dev 21:2731-46inferred by electronic annotationIEAGOIEA

G alpha (q) inhibits PI3K alpha

Reactome DB_ID: 9830158

Reactome DB_ID: 9830058

PI3K alpha [cytosol]

PI3K alpha

Reactome DB_ID: 9826583

UniProt:A0A0G2K344 Pik3ca

Pik3ca

Pik3caFUNCTION Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (By similarity). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology (By similarity). Participates in cellular signaling in response to various growth factors (By similarity). Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinase ligands such as EGF, IGF1, VEGFA and PDGF (By similarity). Also involved in the activation of AKT1 upon stimulation by receptor tyrosine kinase ligand insulin (PubMed:20236230). Involved in signaling via insulin-receptor substrate (IRS) proteins (By similarity). Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity (By similarity). Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF (By similarity). Regulates invadopodia formation through the PDPK1-AKT1 pathway (By similarity). Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway (By similarity). Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway (By similarity). Also has serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS (By similarity). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity).SUBUNIT Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with IRS1 in nuclear extracts. Interacts with RUFY3. Interacts with RASD2. Interacts with APPL1. Interacts with HRAS and KRAS. Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2. Interacts with FAM83B; activates the PI3K/AKT signaling cascade.TISSUE SPECIFICITY Detected in the hypothalamus (at protein level).DOMAIN The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1.SIMILARITY Belongs to the PI3/PI4-kinase family.

UniProtA0A0G2K344

EQUAL

1068

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 9830056

PI3K-regulatory subunits [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPik3r1 [cytosol]

UniProtQ63787Reactome Database ID Release 759830058Database 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=9830058ReactomeR-RNO-198379

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-RNO-198379.1

Reactome DB_ID: 9853240

G-protein alpha (q/11):PI3K alpha [plasma membrane]

G-protein alpha (q/11):PI3K alpha

Reactome DB_ID: 9830158

Reactome DB_ID: 9830058

Reactome Database ID Release 759853240Database 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=9853240ReactomeR-RNO-416356

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-RNO-416356.1Reactome Database ID Release 759853242Database 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=9853242ReactomeR-RNO-416358

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-RNO-416358.1Phospholipase C activation is the classical signalling route for G alpha (q) but an additional mechanism is an inhibitory interaction between G alpha (q) and phosphatidylinositol 3-kinase alpha (PI3K alpha). There are several PI3K subtypes but only the p85 alpha/p110 alpha subtype (PI3K alpha) is a G alpha (q) effector (PMID: 18515384). Activated G alpha (q) inhibits PI3K alpha directly, in a GTP-dependent manner. G alpha(q) binding of PI3K competes with Ras, a PI3K activator (PMID: 16268778).

16268778Pubmed2006Galphaq binds to p110alpha/p85alpha phosphoinositide 3-kinase and displaces RasBallou, LMChattopadhyay, MLi, YScarlata, SLin, RZBiochem J 394:557-6218515384Pubmed2008Galphaq binds two effectors separately in cells: evidence for predetermined signaling pathwaysGolebiewska, UScarlata, SBiophys J 95:2575-82inferred by electronic annotationIEAGOIEA

3.6.5.4

3.6.5.3

3.6.5.2

3.6.5.1

G alpha (q) auto-inactivates by hydrolysing GTP to GDP

Reactome DB_ID: 9830158

Reactome DB_ID: 9830152

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9830158

GO0003924

GO molecular function

Reactome Database ID Release 759853587Database 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=9853587Reactome Database ID Release 759853615Database 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=9853615ReactomeR-RNO-418582

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-RNO-418582.1When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region (Kleuss et al. 1994).

7937899Pubmed1994Mechanism of GTP hydrolysis by G-protein alpha subunitsKleuss, CRaw, ASLee, ESprang, SRGilman, AGProc Natl Acad Sci U S A 91:9828-31inferred by electronic annotationIEAGOIEA

ACTIVATION

Reactome Database ID Release 759853616Database 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=9853616Converted from EntitySet in Reactome

Reactome DB_ID: 9853613

RGS proteins active for G alpha (q) [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRgs3 [plasma membrane]Rgs2 [plasma membrane]Rgs19 [plasma membrane]Rgs18 [plasma membrane]

UniProtP49797UniProtQ9JHX0UniProtO70521UniProtQ4L0E8

Effects of PIP2 hydrolysis

Binding of IP3 to IP3 receptor

Reactome DB_ID: 114520

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

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

ChEBI16595

Reactome DB_ID: 9830431

platelet dense tubular network membraneGO0031095IP3R tetramer [platelet dense tubular network membrane]

IP3R tetramer

Converted from EntitySet in Reactome

Reactome DB_ID: 9830429

IP3R subunits [platelet dense tubular network membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityItpr2 [platelet dense tubular network membrane]Itpr1 [platelet dense tubular network membrane]Itpr3 [platelet dense tubular network membrane]

UniProtP29995UniProtP29994UniProtQ63269Reactome Database ID Release 759830431Database 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=9830431ReactomeR-RNO-418292

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-RNO-418292.1

Reactome DB_ID: 9830433

IP3R tetramer:I(1,4,5)P3:4xCa2+ [platelet dense tubular network membrane]

IP3R tetramer:I(1,4,5)P3:4xCa2+

Reactome DB_ID: 141090

calcium(2+) [ChEBI:29108]

calcium(2+)

ChEBI29108

Reactome DB_ID: 139826

Reactome DB_ID: 9830431

Reactome Database ID Release 759830433Database 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=9830433ReactomeR-RNO-139839

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-RNO-139839.1Reactome Database ID Release 759830581Database 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=9830581ReactomeR-RNO-139941

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-RNO-139941.1The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.

17429043Pubmed2007Inositol trisphosphate receptor Ca2+ release channelsFoskett, JKWhite, CCheung, KHMak, DOPhysiol Rev 87:593-65811413485Pubmed2000The versatility and universality of calcium signallingBerridge, MJLipp, PBootman, MDNat Rev Mol Cell Biol 1:11-21inferred by electronic annotationIEAGOIEA

IP3R tetramer:I(1,4,5)P3:4xCa2+ transports Ca2+ from platelet dense tubular system to cytosol

Transport of Ca++ from platelet dense tubular system to cytoplasmThis event has been computationally inferred from an event that has been demonstrated in another species.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.<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: 139827

platelet dense tubular network lumenGO0031096

Reactome DB_ID: 74016

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9830433

GO0005262

GO molecular function

Reactome Database ID Release 759830434Database 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=9830434Reactome Database ID Release 759830436Database 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=9830436ReactomeR-RNO-139854

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-RNO-139854.1The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it. Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.

1693919Pubmed1990Receptor-activated single channels in intact human plateletsMahaut-Smith, MPSage, SORink, TJJ Biol Chem 265:10479-83inferred by electronic annotationIEAGOIEA

Activation of Protein Kinase C novel isoforms

Converted from EntitySet in Reactome

Reactome DB_ID: 9854680

Protein kinase C, novel isoforms [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPrkcd [cytosol]Prkce [cytosol]Prkcq [cytosol]Prkch [cytosol]

UniProtP09215UniProtP09216UniProtQ9WTQ0UniProtQ64617

Reactome DB_ID: 114519

1,2-diacyl-sn-glycerol [ChEBI:17815]

1,2-diacyl-sn-glycerol

ChEBI17815

Reactome DB_ID: 9854682

Protein kinase C, novel isoforms:DAG [plasma membrane]

Protein kinase C, novel isoforms:DAG

Converted from EntitySet in Reactome

Reactome DB_ID: 9854680

Reactome DB_ID: 114519

Reactome Database ID Release 759854682Database 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=9854682ReactomeR-RNO-426071

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-RNO-426071.1Reactome Database ID Release 759854684Database 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=9854684ReactomeR-RNO-425861

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-RNO-425861.1Activation of the novel Protein Kinase C (nPKC) isoforms (delta, epsilon, eta and theta) requires binding to the membrane lipid diacylglycerol (DAG). nPKC activation is sensitive to DAG concentration.

9601053Pubmed1998The extended protein kinase C superfamilyMellor, HParker, PJBiochem J 332:281-9219033211Pubmed2009Lipid activation of protein kinasesNewton, ACJ Lipid Res 50:S266-719780306478635ISBN2004Protein Kinase C 2nd edDekker, LProtein Kinase C 2nd ed (Book)inferred by electronic annotationIEAGOIEA

DAG activation of TRPC channels

Converted from EntitySet in Reactome

Reactome DB_ID: 9854804

TRPC3/6/7 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTrpc7 [plasma membrane]Trpc3 [plasma membrane]Trpc6 [plasma membrane]

UniProtF1LQF7UniProtQ9JMI9UniProtQ99N78

Reactome DB_ID: 114519

Reactome DB_ID: 9854806

DAG-activated TRPC3/6/7 [plasma membrane]

DAG-activated TRPC3/6/7

Converted from EntitySet in Reactome

Reactome DB_ID: 9854804

Reactome DB_ID: 114519

Reactome Database ID Release 759854806Database 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=9854806ReactomeR-RNO-426179

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-RNO-426179.1Reactome Database ID Release 759854808Database 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=9854808ReactomeR-RNO-426209

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-RNO-426209.1TRPC3, 6 and 7 are non-selective cation channels that are activated by diacylglycerol (DAG) independently of protein kinase C activation by DAG. By analogy with the structures of voltage-regulated calcium channels, TRPC channels are probably tetramers of TRPC protein; heterotetramers within the 3/6/7 group have been observed.

10488066Pubmed1999Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca(2+)-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptorOkada, TInoue, RYamazaki, KMaeda, AKurosaki, TYamakuni, TTanaka, IShimizu, SIkenaka, KImoto, KMori, YJ Biol Chem 274:27359-708986787Pubmed1996On the molecular basis and regulation of cellular capacitative calcium entry: roles for Trp proteinsBirnbaumer, LZhu, XJiang, MBoulay, GPeyton, MVannier, BBrown, DPlatano, DSadeghi, HStefani, EBirnbaumer, MProc Natl Acad Sci U S A 93:15195-20212765690Pubmed2003The TRPC3/6/7 subfamily of cation channelsTrebak, MVazquez, GBird, GSPutney JW, JrCell Calcium 33:451-619930701Pubmed1999Direct activation of human TRPC6 and TRPC3 channels by diacylglycerolHofmann, TObukhov, AGSchaefer, MHarteneck, CGudermann, TSchultz, GNature 397:259-6312032305Pubmed2002Subunit composition of mammalian transient receptor potential channels in living cellsHofmann, TSchaefer, MSchultz, GGudermann, TProc Natl Acad Sci U S A 99:7461-611805119Pubmed2002Cloning and functional expression of human short TRP7, a candidate protein for store-operated Ca2+ influxRiccio, AMattei, CKelsell, REMedhurst, ADCalver, ARRandall, ADDavis, JBBenham, CDPangalos, MNJ Biol Chem 277:12302-9inferred by electronic annotationIEAGOIEA

Arachidonate production from DAG

3.1.1.23

DAG is metabolized by DAGL to 2-AG

Reactome DB_ID: 114519

Reactome DB_ID: 426026

fatty acid [ChEBI:35366]

fatty acid

ChEBI35366

Reactome DB_ID: 426030

2-arachidonoylglycerol [ChEBI:52392]

2-arachidonoylglycerol

ChEBI52392PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 9854740

Diacylglycerol lipase [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDagla [plasma membrane]Daglb [plasma membrane]

UniProtQ5YLM1UniProtP0C1S9GO0047372

GO molecular function

Reactome Database ID Release 759854741Database 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=9854741Reactome Database ID Release 759854743Database 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=9854743ReactomeR-RNO-426032

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-RNO-426032.1Diacylglycerol lipase (DAGL) hydrolyzes diacylglycerol (DAG) at the sn-1 position, producing 2-monoacylglycerols, including 2-arachidonlyglycerol (2-AG) and free fatty acid. This reaction was first characterised for the release of arachidonate from membrane phospholipids in platelets, but is also involved in the spatial and temporal regulation of endocannabinoid signaling in the brain. DAGL exhibits strong selectivity for diacylglycerols over phospholipids, monoacylglycerols, triacylglycerols and fatty acid amides, and prefers the acyl group at sn-1 position to that at sn-2.

19126434Pubmed2008Biology of endocannabinoid synthesis systemWang, JUeda, NProstaglandins Other Lipid Mediat10348910Pubmed1999Purification and characterization of diacylglycerol lipase from human plateletsMoriyama, TUrade, RKito, MJ Biochem 125:1077-85inferred by electronic annotationIEAGOIEA

3.1.1.23

2-AG hydrolysis to arachidonate by MAGL

Reactome DB_ID: 29356

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 426030

Reactome DB_ID: 422506

arachidonic acid [ChEBI:15843]

arachidonic acid

ChEBI15843

Reactome DB_ID: 76116

glycerol [ChEBI:17754]

glycerol

ChEBI17754

Reactome DB_ID: 70106

hydron [ChEBI:15378]

hydron

ChEBI15378PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9854746

UniProt:Q8R431 Mgll

Mgll

Mgl2MgllFUNCTION Converts monoacylglycerides to free fatty acids and glycerol (PubMed:12136125). Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (PubMed:12136125, PubMed:17649977). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth (By similarity).PATHWAY Glycerolipid metabolism; triacylglycerol degradation.SUBUNIT Homodimer.TISSUE SPECIFICITY Ubiquitous. Highly expressed in adipose tissue, adrenal gland, ovary, heart, spleen, lung, skeletal muscle, kidney and testis. Highly expressed throughout the brain.MISCELLANEOUS Requires non-ionic detergent for solubilization.MISCELLANEOUS Short-term inhibition causes analgesia, while long-term inhibition causes tolerance to endocannabinoids acting on brain cannabinoid receptor CNR1, and a reduction in brain cannabinoid receptor CNR1 activity.SIMILARITY Belongs to the AB hydrolase superfamily. Monoacylglycerol lipase family.

UniProtQ8R431

EQUAL

303

EQUAL

Reactome Database ID Release 759854747Database 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=9854747Reactome Database ID Release 759854749Database 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=9854749ReactomeR-RNO-426043

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-RNO-426043.1Monoacylglycerol lipase (MAGL) is a key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol to arachidonate and glycerol. In adipocytes MAGL and hormone-sensitive lipase (LIPE) hydrolyze intracellular triglyceride stores. MAGL may also complement lipoprotein lipase (LPL) in completing hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides.

11470505Pubmed2001Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase geneKarlsson, MReue, KXia, YRLusis, AJLangin, DTornqvist, HHolm, CGene 272:11-816116451Pubmed2005Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampusMakara, JKMor, MFegley, DSzabó, SIKathuria, SAstarita, GDuranti, ATontini, ATarzia, GRivara, SFreund, TFPiomelli, DNat Neurosci 8:1139-417295321Pubmed1981Release of arachidonate from diglyceride in human platelets requires the sequential action of a diglyceride lipase and a monoglyceride lipaseChau, LYTai, HHBiochem Biophys Res Commun 100:1688-9518096503Pubmed2007A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerolBlankman, JLSimon, GMCravatt, BFChem Biol 14:1347-56inferred by electronic annotationIEAGOIEA

3.1.1.23

ABHD6,12 hydrolyse 3AG

Reactome DB_ID: 5694509

3-arachidonoyl-sn-glycerol [ChEBI:75571]

3-arachidonoyl-sn-glycerol

3-monoarachidonoyl-sn-glycerolsn-3-arachidonoyl monoglyceride3-(5Z,8Z,11Z,14Z)-icosatetraenoyl-sn-glycerolMG (0:0/0:0/20:4(n-6))

ChEBI75571

Reactome DB_ID: 29356

Reactome DB_ID: 422506

Reactome DB_ID: 76116

Reactome DB_ID: 70106

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 9903310

ABHD6,12 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityAbhd6 [plasma membrane]Abhd12 [plasma membrane]

UniProtQ5XI64UniProtQ6AYT7Reactome Database ID Release 759903311Database 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=9903311Reactome Database ID Release 759903313Database 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=9903313ReactomeR-RNO-5694462

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-RNO-5694462.1Three members of the serine hydrolase family are involved in the degradation of the endocannabinoid 2-arachidonoylyglycerol (C20:4) (2AG). The major enzymatic route for 2AG inactivation is via hydrolysis, generating arachidonic acid (AA) and glycerol. Two of the serine hydrolases, monoacylglycerol lipases 6 and 12 (ABHD6 and 12), have preference for the 3-acyl isomer of arachidonoylyglycerol (3AG) although they can also hydrolyse 2AG at a lower rate (Navia-Paldanius et al. 2012, Savinainen et al. 2012).

21418147Pubmed2012The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptorsSavinainen, J RSaario, S MLaitinen, J TActa Physiol (Oxf) 204:267-7622969151Pubmed2012Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)Navia-Paldanius, DinaSavinainen, Juha RLaitinen, Jarmo TJ. Lipid Res. 53:2413-24inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 759929272Database 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=9929272ReactomeR-RNO-426048

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-RNO-426048.1Diacylglycerol (DAG) is an important source of arachidonic acid, a signalling molecule and the precursor of the prostaglandins. In human platelet almost all the DAG produced from phosphatidylinositol degradation contains arachidonate (Takamura et al. 1987). DAG is hydrolysed by DAG lipase to 2-arachidonylglycerol (2-AG) which is further hydrolysed by monoacylglycerol lipase. 2-AG is an agonist of cannabinoid receptor 1.

6788766Pubmed1981Diacylglycerol metabolism and arachidonic acid release in human fetal membranes and decidua veraOkazaki, TSagawa, NOkita, JRBleasdale, JEMacDonald, PCJohnston, JMJ Biol Chem 256:7316-219783527605767ISBN2003Biochemistry of signal transduction and regulationKrauss, GerhardBiochemistry of signal transduction and regulation (Book): 25911588122Pubmed2001Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranesSavinainen, JRJärvinen, TLaine, KLaitinen, JTBr J Pharmacol 134:664-723102469Pubmed1987Differential hydrolysis of phospholipid molecular species during activation of human platelets with thrombin and collagenTakamura, HNarita, HPark, HJTanaka, KMatsuura, TKito, MJ Biol Chem 262:2262-9inferred by electronic annotationIEAGOIEA

2.7.1.107

DAG kinase produces phosphatidic acid from DAG

Reactome DB_ID: 114519

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 76108

1,2-diacyl-sn-glycerol 3-phosphate [ChEBI:29089]

1,2-diacyl-sn-glycerol 3-phosphate

ChEBI29089

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 9854853

Diacylglycerol kinase [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDgka [plasma membrane]Dgkg [plasma membrane]Dgkb [plasma membrane]Dgke [plasma membrane]Dgki [plasma membrane]Dgkh [plasma membrane]Dgkz [plasma membrane]Dgkq [plasma membrane]Dgkd [plasma membrane]Dgkk [plasma membrane]

UniProtP51556UniProtP49620UniProtP49621UniProtA0A096UWG9UniProtF1MAB7UniProtD3ZSZ6UniProtO08560UniProtD3ZEY4UniProtF1M5T2UniProtF1LZW2GO0004143

GO molecular function

Reactome Database ID Release 759854854Database 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=9854854Reactome Database ID Release 759854856Database 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=9854856ReactomeR-RNO-426240

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-RNO-426240.1Diacylglycerol kinases (DGKs) are intracellular lipid kinases that use ATP to phosphorylate diacylglycerol (DAG)., generating phosphatidic acid (PA). This lowers membrane DAG levels, regulating signalling proteins that require DAG for membrane association such as Protein Kinase C. PA is a signalling molecule that regulates Raf-1 and PKC zeta, and a substrate for the resynthesis of phosphatidylinositol.

18062770Pubmed2008Diacylglycerol kinases: at the hub of cell signallingMérida, IAvila-Flores, AMerino, EBiochem J 409:1-182175712Pubmed1990Purification, cDNA-cloning and expression of human diacylglycerol kinaseSchaap, Dde Widt, Jvan der Wal, JVandekerckhove, Jvan Damme, JGussow, DPloegh, HLvan Blitterswijk, WJvan der Bend, RLFEBS Lett 275:151-88626548Pubmed1996Raf-1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf-1 in 12-O-tetradecanoylphorbol-13-acetate-stimulated Madin-Darby canine kidney cellsGhosh, SStrum, JCSciorra, VADaniel, LBell, RMJ Biol Chem 271:8472-8011080611Pubmed2000Properties and functions of diacylglycerol kinasesvan Blitterswijk, WJHoussa, BCell Signal 12:595-605inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 759928118Database 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=9928118ReactomeR-RNO-114508

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-RNO-114508.1Hydrolysis of phosphatidyl inositol-bisphosphate (PIP2) by phospholipase C (PLC) produces diacylglycerol (DAG) and inositol triphosphate (IP3). Both are potent second messengers. IP3 diffuses into the cytosol, but as DAG is a hydrophobic lipid it remains within the plasma membrane. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, while DAG activates the conventional and unconventional protein kinase C (PKC) isoforms, facilitating the translocation of PKC from the cytosol to the plasma membrane. The effects of DAG are mimicked by tumor-promoting phorbol esters. DAG is also a precursor for the biosynthesis of prostaglandins, the endocannabinoid 2-arachidonoylglycerol and an activator of a subfamily of TRP-C (Transient Receptor Potential Canonical) cation channels 3, 6, and 7.

17157506Pubmed2007Diacylglycerol, when simplicity becomes complexCarrasco, SMérida, ITrends Biochem Sci 32:27-36inferred by electronic annotationIEAGOIEA

Active Gq binds BTK

Reactome DB_ID: 9830158

Reactome DB_ID: 9882640

UniProt:A0A0G2K134Btk

UniProtA0A0G2K134

EQUAL

659

EQUAL

Reactome DB_ID: 9922965

Active Gq:BTK [plasma membrane]

Active Gq:BTK

Reactome DB_ID: 9830158

Reactome DB_ID: 9882640

EQUAL

659

EQUAL

Reactome Database ID Release 759922965Database 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=9922965ReactomeR-RNO-8964296

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-RNO-8964296.1Reactome Database ID Release 759922967Database 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=9922967ReactomeR-RNO-8964280

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-RNO-8964280.1G-Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins. Upon activation, the Guanine nucleotide-binding protein G(q) subunit alpha class (GNAQ/GNA11/GNA14/GNA15) can bind directly to the THSH3 domain of the non-receptor Tyrosine-protein kinase BTK in vitro and in vivo. This binding results in a conformational change in BTK, which leads to its activation. Physiologically, BTK plays a key role in B lymphocyte development, differentiation and signalling.

11742120Pubmed2002Competing modes of self-association in the regulatory domains of Bruton's tyrosine kinase: intramolecular contact versus asymmetric homodimerizationLaederach, AlainCradic, Kendall WBrazin, Kristine NZamoon, JamillahFulton, D BruceHuang, Xin-YunAndreotti, Amy HProtein Sci. 11:36-459305846Pubmed1997Direct stimulation of Bruton's tyrosine kinase by G(q)-protein alpha-subunitBence, KMa, WKozasa, THuang, X YNature 389:296-99770463Pubmed1998Identification of the binding site for Gqalpha on its effector Bruton's tyrosine kinaseMa, Y CHuang, X YProc. Natl. Acad. Sci. U.S.A. 95:12197-201inferred by electronic annotationIEAGOIEA

BTK in active Gq-BTK complex is activated

Reactome DB_ID: 9922965

Reactome Database ID Release 759922969Database 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=9922969ReactomeR-RNO-8964284

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-RNO-8964284.1G-Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins. Upon activation, the Guanine nucleotide-binding protein G(q) subunit alpha class (GNAQ/GNA11/GNA14/GNA15) can bind directly to the non-receptor Tyrosine-protein kinase BTK. This binding breaks intramolecular interactions in BTK thereby making the kinase domain available for substrates. Physiologically, BTK plays a key role in B lymphocyte development, differentiation and signalling.

inferred by electronic annotationIEAGOIEA

Gq-BTK complex dissociates to Active BTK and Gq

Reactome DB_ID: 9922965

Reactome DB_ID: 9830158

Reactome DB_ID: 9882640

EQUAL

659

EQUAL

Reactome Database ID Release 759922975Database 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=9922975ReactomeR-RNO-8964340

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-RNO-8964340.1G-Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins. Upon activation, the Guanine nucleotide-binding protein G(q) subunit alpha class (GNAQ/GNA11/GNA14/GNA15) can bind to the non-receptor Tyrosine-protein kinase BTK. This binding results in a conformational change in BTK. Subsequently, the structurally modified BTK is released from GNAQ and is now catalytically active. Active BTK can trigger the downstream MAPK p38 pathway. Physiologically, BTK plays a key role in B lymphocyte development, differentiation and signalling.

inferred by electronic annotationIEAGOIEA

Active G alpha (q) binds RGS proteins

Reactome DB_ID: 9830158

Converted from EntitySet in Reactome

Reactome DB_ID: 9923143

RGS1,2,3,4,5,13,16,17,18,19,21 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRgs4 [plasma membrane]Rgs3 [plasma membrane]Rgs1 [plasma membrane]Rgs5 [plasma membrane]Rgs16 [plasma membrane]Rgs2 [plasma membrane]Rgs21 [plasma membrane]Rgs19 [plasma membrane]Rgs18 [plasma membrane]Rgs13 [plasma membrane]Rgs17 [plasma membrane]

UniProtP49799UniProtP97844UniProtP49800UniProtP56700UniProtA0A0G2JZN6UniProtD3ZCS1UniProtF1M0G0

Reactome DB_ID: 9923145

G alpha (q):GTP:RGS [plasma membrane]

G alpha (q):GTP:RGS

Reactome DB_ID: 9830158

Converted from EntitySet in Reactome

Reactome DB_ID: 9923143

Reactome Database ID Release 759923145Database 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=9923145ReactomeR-RNO-8982027

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-RNO-8982027.1Reactome Database ID Release 759923147Database 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=9923147ReactomeR-RNO-8982017

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-RNO-8982017.1G Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins (G proteins). Upon activation, GPCRs can replace the GDP with GTP in the alpha subunit of G proteins. GTP binding modifies the conformation of G alpha proteins and activates them. The Regulator of G protein Signalling (RGS) are GTPase Accelerating Proteins (GAPs) that can directly inhibit the G alpha subunit activity. There are at least 25 different types of RGS proteins known. Several of these RGS proteins (1, 2, 3, 4, 5, 8, 13, 16, 17, 18, 19, 21) can bind and stabilize the transition state for GTP hydrolysis of Guanine nucleotide binding protein G(q) subunit alpha class (GNAQ/GNA11/GNA14/GNA15). Subsequently, this leads to GTP hydrolysis and inactivation of G alpha (q) and terminating downstream signalling (Neubig RR and Siderovski DP et al. 2002, Kach J et al., 2012). The primary function of G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation.

18434541Pubmed2008Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunitsSoundararajan, MeeraWillard, Francis SKimple, Adam JTurnbull, Andrew PBall, Linda JSchoch, Guillaume AGileadi, CarinaFedorov, Oleg YDowler, Elizabeth FHigman, Victoria AHutsell, Stephanie QSundström, MDoyle, DASiderovski, David PProc. Natl. Acad. Sci. U.S.A. 105:6457-6212120503Pubmed2002Regulators of G-protein signalling as new central nervous system drug targetsNeubig, Richard RSiderovski, David PNat Rev Drug Discov 1:187-97inferred by electronic annotationIEAGOIEA

3.6.5.4

3.6.5.3

3.6.5.2

3.6.5.1

G alpha (q) in G (q):RGS complex is inactivated

Reactome DB_ID: 9923145

Reactome DB_ID: 9923163

G alpha (q):GDP:RGS [plasma membrane]

G alpha (q):GDP:RGS

Converted from EntitySet in Reactome

Reactome DB_ID: 9923143

Reactome DB_ID: 29420

Converted from EntitySet in Reactome

Reactome DB_ID: 9830150

Reactome Database ID Release 759923163Database 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=9923163ReactomeR-RNO-8982013

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-RNO-8982013.1

Reactome DB_ID: 29372

hydrogenphosphate [ChEBI:43474]

hydrogenphosphate

[PO3(OH)](2-)HYDROGENPHOSPHATE IONhydrogen phosphate[P(OH)O3](2-)HPO4(2-)phosphateINORGANIC PHOSPHATE GROUP

ChEBI43474PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9923145

Reactome Database ID Release 759923164Database 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=9923164Reactome Database ID Release 759923166Database 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=9923166ReactomeR-RNO-8982025

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-RNO-8982025.1G Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins (G proteins). Upon activation, GPCRs can replace the GDP with GTP in the alpha subunit of G proteins. GTP binding modifies the conformation of G alpha proteins and activates them. The Regulator of G protein Signalling (RGS) are GTPase Accelerating Proteins (GAPs) that can directly inhibit the G alpha subunit activity. There are at least 25 different types of RGS proteins known. Several of these RGS proteins (1, 2, 3, 4, 5, 8, 13, 16, 17, 18, 19, 21) can bind and stabilize the transition state of Guanine nucleotide binding protein G(q) subunit alpha class (GNAQ/GNA11/GNA14/GNA15). Following this, the RGS domain of the proteins exert GAP activity on G alpha (q) and allosterically modulate residues within G-alpha subunit to accelerate the intrinsic GTPase activity that hydrolyses GTP to GDP. This inactivates G alpha (q) and terminates downstream signalling (Neubig & Siderovski 2002, Kach et al. 2012). The primary function of G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation.

inferred by electronic annotationIEAGOIEA

G alpha (q):RGS dissociates to inactive G alpha (q)

Reactome DB_ID: 9923163

Converted from EntitySet in Reactome

Reactome DB_ID: 9923143

Reactome DB_ID: 9830152

Reactome Database ID Release 759923168Database 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=9923168ReactomeR-RNO-8982026

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-RNO-8982026.1G Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins (G proteins). Upon activation, GPCRs can replace the GDP with GTP in the alpha subunit of G proteins. GTP binding modifies the conformation of G alpha proteins and activates them. The Regulator of G protein Signalling (RGS) are GTPase Accelerating Proteins (GAPs) that can directly inhibit the G alpha subunit activity. There are at least 25 different types of RGS proteins known. Several of these RGS proteins (1, 2, 3, 4, 5, 8, 13, 16, 17, 18, 19, 21) can bind and stabilize the transition state of Guanine nucleotide binding protein G(q) subunit alpha class (GNAQ/GNA11/GNA14/GNA15). Subsequently, the RGS domain in the complex facilitates the hydrolyses of G alpha (q):GTP to G alpha (q):GDP. Following this, the complex dissociates releasing inactive G alpha (q) (Neubig & Siderovski 2002, Kach et al. 2012). The primary function of G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation.

inferred by electronic annotationIEAGOIEA

3.1.4.3

PLC-beta hydrolyses PIP2 to DAG and IP3

Reactome DB_ID: 9830356

PLC-beta:G-alpha(q/11):PIP2 [plasma membrane]

PLC-beta:G-alpha(q/11):PIP2

Reactome DB_ID: 9830354

PLC beta:G alpha (q/11) [plasma membrane]

PLC beta:G alpha (q/11)

Converted from EntitySet in Reactome

Reactome DB_ID: 9829222

PLC-beta [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPlcb1 [cytosol]Plcb4 [cytosol]Plcb3 [cytosol]Plcb2 [cytosol]

UniProtP10687UniProtQ9QW07UniProtQ99JE6UniProtO89040

Reactome DB_ID: 9830158

Reactome Database ID Release 759830354Database 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=9830354ReactomeR-RNO-398158

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-RNO-398158.1

Reactome DB_ID: 179856

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

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

PIP2

ChEBI18348Reactome Database ID Release 759830356Database 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=9830356ReactomeR-RNO-8983508

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-RNO-8983508.1

Reactome DB_ID: 9830358

PLC-beta:G-alpha(q/11):DAG:IP3 [plasma membrane]

PLC-beta:G-alpha(q/11):DAG:IP3

Reactome DB_ID: 9830354

Reactome DB_ID: 114520

Reactome DB_ID: 114519

Reactome Database ID Release 759830358Database 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=9830358ReactomeR-RNO-8983509

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-RNO-8983509.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9830354

GO0004629

GO molecular function

Reactome Database ID Release 759830359Database 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=9830359Reactome Database ID Release 759830361Database 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=9830361ReactomeR-RNO-114688

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-RNO-114688.1Phospholipase C (PLC) isozymes are a group of related proteins that cleave the polar head group from inositol phospholipids, typically in response to signals from cell surface receptors. They hydrolyze the highly phosphorylated lipid phosphatidylinositol 4,5-bisphosphate (PIP2) generating two products: inositol 1,4,5-trisphosphate (IP3), a universal calcium-mobilizing second messenger, and diacylglycerol (DAG), an activator of protein kinase C. PLC-beta isoforms are regulated by heterotrimeric GTP-binding proteins. PLC-beta 1 and 3 are widely expressed, with the highest concentrations found in (differing) specific regions of the brain. PLC-beta 2 is expressed at highest levels in cells of hematopoeitic origin; it is involved in leukocyte signaling and host defense. PLC-beta 4 is highly concentrated in cerebellar Purkinje and granule cells, the median geniculate body, whose axons terminate in the auditory cortex, and the lateral geniculate nucleus, where most retinal axons terminate in a visuotopic representation of each half of the visual field.

2841328Pubmed1988Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human plateletsBanno, YYada, YNozawa, YJ Biol Chem 263:11459-6511015615Pubmed2000Structure, function, and control of phosphoinositide-specific phospholipase CRebecchi, MJPentyala, SNPhysiol Rev 80:1291-335inferred by electronic annotationIEAGOIEA

Gastrin-CREB signalling pathway via PKC and MAPK

Gastrin binds to CCK-B receptor

Reactome DB_ID: 9847532

UniProt:P30553Cckbr

UniProtP30553

EQUAL

447

EQUAL

Reactome DB_ID: 9847880

UniProt:P04563Gast

UniProtP04563

EQUAL

Reactome DB_ID: 9847882

Gastrin:CCKBR [plasma membrane]

Gastrin:CCKBR

Reactome DB_ID: 9847532

EQUAL

447

EQUAL

Reactome DB_ID: 9847880

EQUAL

Reactome Database ID Release 759847882Database 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=9847882ReactomeR-RNO-870262

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-RNO-870262.1Reactome Database ID Release 759860061Database 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=9860061ReactomeR-RNO-870269

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-RNO-870269.1Gastrin receptors (gastric cholecystokinin B receptor, CCK-BR) mediate acid secretion from parietal cells, release of histamine from enterochromaffin-like (ECL) cells and contraction of smooth muscle (Ito et al. 1993).The hormone gastrin is the central regulator of gastric acid secretion and in addition, plays a prominent role in regulation of growth and differentiation of gastric and colonic mucosa.

8349705Pubmed1993Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrinIto, MMatsui, TTaniguchi, TTsukamoto, TMurayama, TArima, NNakata, HChiba, TChihara, KJ Biol Chem 268:18300-5inferred by electronic annotationIEAGOIEA

EGFR Transactivation by Gastrin

Diacylgycerol activates Protein kinase C, alpha type

Reactome DB_ID: 9829413

UniProt:P05696Prkca

UniProtP05696

EQUAL

672

EQUAL

Reactome DB_ID: 114519

Reactome DB_ID: 9853009

Protein Kinase C, alpha type: DAG [plasma membrane]

Protein Kinase C, alpha type: DAG

Reactome DB_ID: 9829413

EQUAL

672

EQUAL

Reactome DB_ID: 114519

Reactome Database ID Release 759853009Database 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=9853009ReactomeR-RNO-422275

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-RNO-422275.1Reactome Database ID Release 759853025Database 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=9853025ReactomeR-RNO-400015

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-RNO-400015.1Diacylglycerol, produced by PLC beta-mediated PIP2 hydrolysis in G alpha (q) signalling, remains in the plasma membrane and binds Protein Kinase C alpha (PKC-alpha), causing PKC-alpha to translocate from the cytosol to the plasma membrane. PKC-alpha is thereby activated and phosphorylates target proteins.

11997388Pubmed2002Interplay between calcium, diacylglycerol, and phosphorylation in the spatial and temporal regulation of PKCalpha-GFPTanimura, AkihikoNezu, AkihiroMorita, TakaoHashimoto, NoboruTojyo, YosukeJ. Biol. Chem. 277:29054-6211588141Pubmed2001Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell functionGilon, PHenquin, JCEndocr Rev 22:565-604inferred by electronic annotationIEAGOIEA

2.7.11.13

Activated PKC-alpha activate MMP3

Reactome DB_ID: 9882453

UniProt:P03957Mmp3

UniProtP03957

EQUAL

477

EQUAL

Reactome DB_ID: 9871038

100

EQUAL

477

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9853009

GO0004697

GO molecular function

Reactome Database ID Release 759882454Database 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=9882454Reactome Database ID Release 759882456Database 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=9882456ReactomeR-RNO-2179413

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-RNO-2179413.1Gastrin activated PKC pathway leads to the induction of matrix metalloproteinase 3 (MMP3) synthesis (Reuben et al. 2002). The cleavage and autocatalysis steps to obtain the fully activated form of MMP3 have been omitted here.

11836255Pubmed2002Molecular mechanism of the induction of metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals. Role of calcium-dependent protein kinase C alphaReuben, PMBrogley, MASun, YCheung, HSJ Biol Chem 277:15190-8inferred by electronic annotationIEAGOIEA

Mature HBEGF binds to EGFR, triggering dimerisation and autophosphorylation of the receptor

Reactome DB_ID: 9836530

UniProt:Q06175Hbegf

UniProtQ06175

EQUAL

148

EQUAL

Reactome DB_ID: 9836502

UniProt:G3V6K6Egfr

UniProtG3V6K6

EQUAL

1210

EQUAL

Reactome DB_ID: 9882444

HB-EGF:p-6Y-EGFR dimer [plasma membrane]

HB-EGF:p-6Y-EGFR dimer

Reactome DB_ID: 9882442

HB-EGF:p-6Y-EGFR [plasma membrane]

HB-EGF:p-6Y-EGFR

Reactome DB_ID: 9836530

EQUAL

148

EQUAL

Reactome DB_ID: 9836580

O4'-phospho-L-tyrosine at 992 (in Homo sapiens)

992

EQUAL

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

O4'-phospho-L-tyrosine at 1045 (in Homo sapiens)

1045

EQUAL

O4'-phospho-L-tyrosine at 1068 (in Homo sapiens)

1068

EQUAL

O4'-phospho-L-tyrosine at 1086 (in Homo sapiens)

1086

EQUAL

O4'-phospho-L-tyrosine at 1148 (in Homo sapiens)

1148

EQUAL

O4'-phospho-L-tyrosine at 1173 (in Homo sapiens)

1173

EQUAL

1210

EQUAL

Reactome Database ID Release 759882442Database 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=9882442ReactomeR-RNO-2179388

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-RNO-2179388.1Reactome Database ID Release 759882444Database 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=9882444ReactomeR-RNO-2179410

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-RNO-2179410.1Reactome Database ID Release 759882446Database 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=9882446ReactomeR-RNO-2179387

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-RNO-2179387.1The heparin-binding EGF growth factor (HBEGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor EGFR/ErbB1 and ErbB4 (not shown here) (Higashiyama et al. 1991, Elenius et al. 1997). The details which describe receptor dimerisation on ligand binding and autophosphorylation from experiments in mice have been omitted here.

1840698Pubmed1991A heparin-binding growth factor secreted by macrophage-like cells that is related to EGFHigashiyama, SAbraham, JAMiller, JFiddes, JCKlagsbrun, MichaelScience 251:936-99135143Pubmed1997Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferationElenius, KPaul, SAllison, GSun, JKlagsbrun, MichaelEMBO J 16:1268-78inferred by electronic annotationIEAGOIEA

GRB2:SOS1 binds to HBEGF:p-Y-EGFR

Reactome DB_ID: 9826568

GRB2-1:SOS1 [cytosol]

GRB2-1:SOS1

Reactome DB_ID: 9826563

UniProt:P62994 Grb2

Grb2

AshGrb2FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect. Interacts with IRS4 (when Tyr-phosphorylated). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains. It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1. Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1. Interacts with phosphorylated MET. Interacts with phosphorylated TOM1L1. Interacts with the phosphorylated C-terminus of SH2B2. Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation. Interacts with NISCH, PTPNS1 and REPS2. Interacts with syntrophin SNTA1. Interacts (via SH3 domains) with REPS1. Interacts (via SH3 domains) with PIK3C2B. Interacts with CBL and CBLB. Interacts with AJUBA and CLNK. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2. Interacts with PTPN11. Interacts with PRNP. Interacts with RALGPS1. Interacts also with HCST. Interacts with KDR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with GAPT and PTPRE. Interacts (via SH2 domain) with KIF26A. Interacts (via SH3 2) with GAB2. Interacts with ADAM15. Interacts with THEMIS2. Interacts (via SH2 domain) with AXL (phosphorylated). Interacts (via SH2 domain) with KIT (phosphorylated). Interacts with PTPRJ and BCR. Interacts with PTPN23. Interacts with FLT4 (tyrosine phosphorylated). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration. Part of a complex including TNK2, GRB2 and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2. Interacts with ERBB4. Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with PTK2/FAK1 (tyrosine phosphorylated). Interacts with PTK2B/PYK2 (tyrosine phosphorylated). Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation on SCIMP 'Tyr-58' (By similarity). Interacts (via SH3 domains) with GAREM1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation. Interacts with DAB2. Interacts with TESPA1. Interacts with THEMIS. Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1. Interacts with CD28. Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA. Interacts with ASAP3 (phosphorylated form) (By similarity). Interacts (via SH2 domain) with CSF1R and IRS1 (tyrosine phosphorylated) (PubMed:8262059, PubMed:8388384). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By similarity). Interacts with PTPRO (phosphorylated form) (By similarity). Interacts with PTPRB (phosphorylated form) (By similarity). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (By similarity). Interacts with DENND2B (By similarity). Interacts (via SH3 domain) with ZDHHC19 (via SH3-binding motif); leading to recruit STAT3 (By similarity).TISSUE SPECIFICITY Wide tissue distribution.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family.

UniProtP62994

EQUAL

217

EQUAL

Reactome DB_ID: 9826566

UniProt:D4A3T0 Sos1rCG_62427Sos1

UniProtD4A3T0

EQUAL

1333

EQUAL

Reactome Database ID Release 759826568Database 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=9826568ReactomeR-RNO-109797

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-RNO-109797.1

Reactome DB_ID: 9882444

Reactome DB_ID: 9882448

GRB2:SOS1:HB-EGF:p-6Y-EGFR [plasma membrane]

GRB2:SOS1:HB-EGF:p-6Y-EGFR

Reactome DB_ID: 9826568

Reactome DB_ID: 9882444

Reactome Database ID Release 759882448Database 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=9882448ReactomeR-RNO-2179409

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-RNO-2179409.1Reactome Database ID Release 759882458Database 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=9882458ReactomeR-RNO-2179415

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-RNO-2179415.1Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 autophosphorylation sites on the receptor (Batzer et al. 1994, Okutani et al. 1994).

7527043Pubmed1994Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cellsOkutani, TOkabayashi, YKido, YSugimoto, YSakaguchi, KMatuoka, KTakenawa, TKasuga, MJ Biol Chem 269:31310-47518560Pubmed1994Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptorBatzer, AGRotin, DUrena, JMSkolnik, EYSchlessinger, JMol Cell Biol 14:5192-201inferred by electronic annotationIEAGOIEA

SOS1-mediated nucleotide exchange of RAS (HB-EFG-initiated)

Reactome DB_ID: 29438

Reactome DB_ID: 9836669

p21 RAS:GDP [plasma membrane]

p21 RAS:GDP

Reactome DB_ID: 29420

Converted from EntitySet in Reactome

Reactome DB_ID: 9834947

mature p21 RAS [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHras [plasma membrane]Nras [plasma membrane]Kras [plasma membrane]

UniProtP20171UniProtQ04970UniProtP08644Reactome Database ID Release 759836669Database 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=9836669ReactomeR-RNO-109796

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-RNO-109796.1

Reactome DB_ID: 9834949

p21 RAS:GTP [plasma membrane]

p21 RAS:GTP

Reactome DB_ID: 29438

Converted from EntitySet in Reactome

Reactome DB_ID: 9834947

Reactome Database ID Release 759834949Database 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=9834949ReactomeR-RNO-109783

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-RNO-109783.1

Reactome DB_ID: 29420

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 9882448

GO0005088

GO molecular function

Reactome Database ID Release 759882449Database 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=9882449Reactome Database ID Release 759882451Database 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=9882451ReactomeR-RNO-2179407

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-RNO-2179407.1SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP) (Chardin et al. 1993).

8493579Pubmed1993Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2Chardin, PCamonis, JHGale, NWVan Aelst, LSchlessinger, JWigler, Michael HBar-Sagi, DafnaScience 260:1338-43inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 759929210Database 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=9929210ReactomeR-RNO-2179392

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-RNO-2179392.1Gastrin, through the action of diacylglycerol produced from downstream G alpha (q) events, transactivates EGFR via a PKC-mediated pathway by activation of MMP3 (Matrix Metalloproteinase 3) which allows formation of mature HBEGF (heparin-binding epidermal growth factor) by cleaving pro-HBEGF. Mature HBEGF is then free to bind the EGFR, resulting in EGFR activation (Dufresne et al. 2006, Liebmann 2011).

16816139Pubmed2006Cholecystokinin and gastrin receptorsDufresne, MSeva, CFourmy, DPhysiol Rev 86:805-4720398727Pubmed2011EGF receptor activation by GPCRs: an universal pathway reveals different versionsLiebmann, CMol Cell Endocrinol 331:222-31inferred by electronic annotationIEAGOIEA

2.7.11

ERK1/2/5 activate RSK1/2/3

Converted from EntitySet in Reactome

Reactome DB_ID: 9839943

nucleoplasmGO0005654

Ribosomal protein S6 kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRps6ka3 [nucleoplasm]Rps6ka2 [nucleoplasm]Rps6ka1 [nucleoplasm]

UniProtD3Z8E0UniProtF1M7N7UniProtQ63531

Reactome DB_ID: 29358

Converted from EntitySet in Reactome

Reactome DB_ID: 9839965

Phospho-Ribosomal protein S6 kinase [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-Rps6ka2 [nucleoplasm]phospho-Rps6ka1 [nucleoplasm]phospho-Rps6ka3 [nucleoplasm]

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 9839971

p-MAPK3/MAPK1/MAPK7 dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

GO0004674

GO molecular function

Reactome Database ID Release 759839972Database 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=9839972Reactome Database ID Release 759839974Database 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=9839974ReactomeR-RNO-198746

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-RNO-198746.1The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK. RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398. Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2.

12832467Pubmed2003Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activityRoux, PPRichards, SABlenis, JMol Cell Biol 23:4796-80416626623Pubmed2006The MAP kinase ERK5 binds to and phosphorylates p90 RSKRanganathan, APearson, GWChrestensen, CASturgill, TWCobb, MHArch Biochem Biophys 449:8-16inferred by electronic annotationIEAGOIEA

2.7.11

RSK1/2/3 phosphorylates CREB at Serine 133

Reactome DB_ID: 29358

Reactome DB_ID: 379798

UniProt:P15337 Creb1

Creb1

Creb1Creb-1FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells (By similarity).SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3 (By similarity). When phosphorylated on Ser-119, binds CREBBP. Interacts with ARRB1. Interacts (phosphorylated form) with TOX3. Binds to HIPK2 (By similarity). Interacts with SGK1 (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (By similarity). Forms a complex with KMT2A and CREBBP (By similarity).PTM Phosphorylation of Ser-119 allows CREBBP binding. Stimulated by phosphorylation. Phosphorylation of both Ser-128 and Ser-119 in the SCN regulates the activity of CREB and participate in circadian rhythm generation (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1. Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). Phosphorylated by TSSK4 on Ser-119 (By similarity).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization (By similarity).SIMILARITY Belongs to the bZIP family.

UniProtP15337

EQUAL

341

EQUAL

Reactome DB_ID: 379806

O-phospho-L-serine at 133

133

EQUAL

O-phospho-L-serine [MOD:00046]

EQUAL

341

EQUAL

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 9839965

Reactome Database ID Release 759840966Database 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=9840966Reactome Database ID Release 759840968Database 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=9840968ReactomeR-RNO-199895

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-RNO-199895.1CREB is phosphorylated at Serine 133 by RSK1/2/3.

9770464Pubmed1998Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos geneDe Cesare, DJacquot, SHanauer, ASassone-Corsi, PProc Natl Acad Sci U S A 95:12202-7inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 759928772Database 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=9928772ReactomeR-RNO-881907

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-RNO-881907.1Gastrin is a hormone whose main function is to stimulate secretion of hydrochloric acid by the gastric mucosa, which results in gastrin formation inhibition. This hormone also acts as a mitogenic factor for gastrointestinal epithelial cells. Gastrin has two biologically active peptide forms, G34 and G17.Gastrin gene expression is upregulated in both a number of pre-malignant conditions and in established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical gastrin cholecystokinin B receptor CCK-BR, its isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion (Wank 1995, de Weerth et al. 1999, Grabowska & Watson 2007)

17698287Pubmed2007Role of gastrin peptides in carcinogenesisGrabowska, AMWatson, SACancer Lett 257:1-157491953Pubmed1995Cholecystokinin receptorsWank, SAAm J Physiol 269:G628-4610413847Pubmed1999[Receptors for cholecystokinin and gastrin]de Weerth, ABläker, Mvon Schrenck, TZ Gastroenterol 37:389-401inferred by electronic annotationIEAGOIEA

Reactome Database ID Release 759928104Database 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=9928104ReactomeR-RNO-416476

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-RNO-416476.1The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gq participates in many other signalling events including direct interaction with RhoGEFs that stimulate RhoA activity and inhibition of PI3K. Both in vitro and in vivo, the G-protein Gq seems to be the predominant mediator of the activation of platelets. Moreover, G alpha (q) can stimulate the activation of Burton tyrosine kinase (Ma Y C et al. 1998). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (z) (Soundararajan M et al. 2008).

9296496Pubmed1997Defective platelet activation in G alpha(q)-deficient miceOffermanns, SToombs, CFHu, YHSimon, MINature 389:183-619212139Pubmed2009Functions and regulatory mechanisms of Gq-signaling pathwaysMizuno, NItoh, HNeurosignals 17:42-5416102047Pubmed2005Protease-activated receptors in hemostasis, thrombosis and vascular biologyCoughlin, SRJ Thromb Haemost 3:1800-14inferred by electronic annotationIEAGOIEA