The 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).
View original pathway at:Reactome.
Ferguson KM, Higashijima T, Smigel MD, Gilman AG.; ''The influence of bound GDP on the kinetics of guanine nucleotide binding to G proteins.''; PubMedEurope PMCScholia
Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ.; ''The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids.''; PubMedEurope PMCScholia
Kach J, Sethakorn N, Dulin NO.; ''A finer tuning of G-protein signaling through regulated control of RGS proteins.''; PubMedEurope PMCScholia
Mellor H, Parker PJ.; ''The extended protein kinase C superfamily.''; PubMedEurope PMCScholia
Dulin NO, Sorokin A, Reed E, Elliott S, Kehrl JH, Dunn MJ.; ''RGS3 inhibits G protein-mediated signaling via translocation to the membrane and binding to Galpha11.''; PubMedEurope PMCScholia
Oldham WM, Hamm HE.; ''Structural basis of function in heterotrimeric G proteins.''; PubMedEurope PMCScholia
Laederach A, Cradic KW, Brazin KN, Zamoon J, Fulton DB, Huang XY, Andreotti AH.; ''Competing modes of self-association in the regulatory domains of Bruton's tyrosine kinase: intramolecular contact versus asymmetric homodimerization.''; PubMedEurope PMCScholia
Gagnon AW, Murray DL, Leadley RJ.; ''Cloning and characterization of a novel regulator of G protein signalling in human platelets.''; PubMedEurope PMCScholia
Kleuss C, Raw AS, Lee E, Sprang SR, Gilman AG.; ''Mechanism of GTP hydrolysis by G-protein alpha subunits.''; PubMedEurope PMCScholia
Soundararajan M, Willard FS, Kimple AJ, Turnbull AP, Ball LJ, Schoch GA, Gileadi C, Fedorov OY, Dowler EF, Higman VA, Hutsell SQ, Sundström M, Doyle DA, Siderovski DP.; ''Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits.''; PubMedEurope PMCScholia
Dupré DJ, Robitaille M, Rebois RV, Hébert TE.; ''The role of Gbetagamma subunits in the organization, assembly, and function of GPCR signaling complexes.''; PubMedEurope PMCScholia
Hubbard KB, Hepler JR.; ''Cell signalling diversity of the Gqalpha family of heterotrimeric G proteins.''; PubMedEurope PMCScholia
Butkowski RJ, Elion J, Downing MR, Mann KG.; ''Primary structure of human prethrombin 2 and alpha-thrombin.''; PubMedEurope PMCScholia
Ma YC, Huang XY.; ''Identification of the binding site for Gqalpha on its effector Bruton's tyrosine kinase.''; PubMedEurope PMCScholia
de Weerth A, Bläker M, von Schrenck T.; ''[Receptors for cholecystokinin and gastrin]''; PubMedEurope PMCScholia
Ballou LM, Chattopadhyay M, Li Y, Scarlata S, Lin RZ.; ''Galphaq binds to p110alpha/p85alpha phosphoinositide 3-kinase and displaces Ras.''; PubMedEurope PMCScholia
Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR.; ''RGS2/G0S8 is a selective inhibitor of Gqalpha function.''; PubMedEurope PMCScholia
Chen B, Leverette RD, Schwinn DA, Kwatra MM.; ''Human G(alpha q): cDNA and tissue distribution.''; PubMedEurope PMCScholia
Shankaranarayanan A, Thal DM, Tesmer VM, Roman DL, Neubig RR, Kozasa T, Tesmer JJ.; ''Assembly of high order G alpha q-effector complexes with RGS proteins.''; PubMedEurope PMCScholia
Amatruda TT, Steele DA, Slepak VZ, Simon MI.; ''G alpha 16, a G protein alpha subunit specifically expressed in hematopoietic cells.''; PubMedEurope PMCScholia
Le Y, Gong W, Tiffany HL, Tumanov A, Nedospasov S, Shen W, Dunlop NM, Gao JL, Murphy PM, Oppenheim JJ, Wang JM.; ''Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1.''; PubMedEurope PMCScholia
Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMedEurope PMCScholia
Su SB, Gong W, Gao JL, Shen W, Murphy PM, Oppenheim JJ, Wang JM.; ''A seven-transmembrane, G protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells.''; PubMedEurope PMCScholia
Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMedEurope PMCScholia
Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ.; ''Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex.''; PubMedEurope PMCScholia
Tiruppathi C, Yan W, Sandoval R, Naqvi T, Pronin AN, Benovic JL, Malik AB.; ''G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells.''; PubMedEurope PMCScholia
Wang J, Ducret A, Tu Y, Kozasa T, Aebersold R, Ross EM.; ''RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz gtpase-activating protein subfamily.''; PubMedEurope PMCScholia
Degen SJ, Davie EW.; ''Nucleotide sequence of the gene for human prothrombin.''; PubMedEurope PMCScholia
Mizuno N, Itoh H.; ''Functions and regulatory mechanisms of Gq-signaling pathways.''; PubMedEurope PMCScholia
Golebiewska U, Scarlata S.; ''Galphaq binds two effectors separately in cells: evidence for predetermined signaling pathways.''; PubMedEurope PMCScholia
Dowal L, Provitera P, Scarlata S.; ''Stable association between G alpha(q) and phospholipase C beta 1 in living cells.''; PubMedEurope PMCScholia
Carman CV, Parent JL, Day PW, Pronin AN, Sternweis PM, Wedegaertner PB, Gilman AG, Benovic JL, Kozasa T.; ''Selective regulation of Galpha(q/11) by an RGS domain in the G protein-coupled receptor kinase, GRK2.''; PubMedEurope PMCScholia
Sallese M, Mariggiò S, D'Urbano E, Iacovelli L, De Blasi A.; ''Selective regulation of Gq signaling by G protein-coupled receptor kinase 2: direct interaction of kinase N terminus with activated galphaq.''; PubMedEurope PMCScholia
Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G.; ''Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120.''; PubMedEurope PMCScholia
Grabowska AM, Watson SA.; ''Role of gastrin peptides in carcinogenesis.''; PubMedEurope PMCScholia
Singer AU, Waldo GL, Harden TK, Sondek J.; ''A unique fold of phospholipase C-beta mediates dimerization and interaction with G alpha q.''; PubMedEurope PMCScholia
Rebecchi MJ, Pentyala SN.; ''Structure, function, and control of phosphoinositide-specific phospholipase C.''; PubMedEurope PMCScholia
Rubio JP, Levy ER, Dobson-Stone C, Monaco AP.; ''Genomic organization of the human galpha14 and Galphaq genes and mutation analysis in chorea-acanthocytosis (CHAC).''; PubMedEurope PMCScholia
Siderovski DP, Willard FS.; ''The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits.''; PubMedEurope PMCScholia
Neubig RR, Siderovski DP.; ''Regulators of G-protein signalling as new central nervous system drug targets.''; PubMedEurope PMCScholia
Hydrolysis 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.
This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
The classical role of the G-protein beta/gamma dimer was believed to be the inactivation of the alpha subunit, Gbeta/gamma was viewed as a negative regulator of Galpha signalling. It is now known that Gbeta/gamma subunits can directly modulate many effectors, including some also regulated by G alpha.
Gastrin 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)
Phospholipase 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.
G 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.
The active form of G protein alpha subunit q (Gq-alpha) was found to activate phospholipase C beta-1 (PLC-beta1), in investigations using bovine membranes. Subsequently, all 4 human isoforms have been shown to be activated by Gq, though activation of PLCbeta-4 is limited. In recombinant assays, several activated rat G alpha q family members were found to stimulate human PLC-beta isoforms with the same rank order of decreasing potency. PLC-beta1 stimulation was slightly more than for PLC-beta3; PLC-beta3 stimulation was 10-fold greater than for beta-2. PLC-beta2 is expressed specifically in hematopoietic cells. PLC-beta acts directly on Gq to accelerate hydrolysis of bound GTP, thus PLC-betas are GTPase activating proteins (GAPs). The crystal structure of the C-terminal region from Turkey PLC-beta, revealed a novel fold composed almost entirely of three long helices forming a coiled-coil that dimerizes along its long axis in an antiparallel orientation. The extent of the dimer interface and gel exclusion chromatography data suggest that PLC-betas are functionally dimeric.
The 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.
Phospholipase 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).
GRKs are serine/threonine kinases that phosphorylate GPCRs leading to receptor desensitization. GRK5 appears to be the predominant regulator of PAR1 desensitization in endothelial cells.
GRK2 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.
When 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).
The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (q) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008).
The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active G alpha (q) subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (q):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates.
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
(q/11):Trio family
RhoGEFssignalling pathway
via PKC and MAPKG-protein Gq/11
(inactive)complexes that activate
Gq/11:Heterotrimeric G-protein Gq (active)complexes that activate
Gq/11:Heterotrimeric G-protein Gq (inactive)complexes that
activate Gq/11Annotated Interactions
(q/11):Trio family
RhoGEFsG-protein Gq/11
(inactive)G-protein Gq/11
(inactive)complexes that activate
Gq/11:Heterotrimeric G-protein Gq (active)complexes that activate
Gq/11:Heterotrimeric G-protein Gq (active)complexes that activate
Gq/11:Heterotrimeric G-protein Gq (inactive)complexes that activate
Gq/11:Heterotrimeric G-protein Gq (inactive)complexes that activate
Gq/11:Heterotrimeric G-protein Gq (inactive)complexes that
activate Gq/11