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Development EDNRB signaling

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Development EDNRB signaling

EDNRB signaling

Endothelin receptor type B ( EDNRB ) belongs to the guanine nucleotide bindingprotein (G-protein) coupled receptor family. Endothelin-1 is most investigatedphysiological ligand of EDNRB [1]. EDNRB binds to many typesof the G-proteins but the main physiological consequence is exerted via its binding tothe G-protein alpha-q/11 and G-protein alpha-i family subunits [2], [3], [4].

Scaffolding Caveolin 1, caveolae protein, 22kDa ( Caveolin-1 ) interacts withEDNRB. EDNRB bound to Caveolin-1 is targeted to caveolae. UponEndothelin-1 stimulation, EDNRB dissociates from Caveolin-1 andexits from the caveolae. Caveolae localization of EDNRB is one of the mechanismsto ensure the balance of EDNRB -mediated signal transduction [5].

ENDRB stimulation by Endothelin-1 ( and, possibly, Endothelin-3) significantly enhances activity of Nitric oxide synthase 3 ( eNOS )which catalyzes Nitric Oxide synthesis from L-arginine [6],[7]. The mechanism of Nitric Oxide production in this case includesthe following steps. Endothelin - stimulated ENDRB activates G-proteinbeta/gamma dissociation from complex with G-protein alpha-i family.G-protein beta/gamma activates Phosphatidylinositol 3 kinase (PI3K) ( mostprobably, Phosphoinositide-3-kinase, regulatory subunit 5 ( PI3K reg class IB(p101) ) and Phosphoinositide-3-kinase, catalytic, gamma polypeptide ( PI3K catclass IB (p110-gamma) ), which products of PtdIns(3,4,5)P3 fromPtdIns(4,5)P2. PtdIns(4,5)P2, in turn, recruits v-akt murine thymomaviral oncogene homolog 1 ( AKT(PKB) ), which activates eNOS byphosphorylation and thus enhances Nitric Oxide production. Enhanced Nitricoxide production during EDNRB stimulation results in smooth muscle andvascular relaxation [7]. Nitric Oxide, in turn, enhancesintracellular concentration of cGMP, most likely by activation of the Guanylatecyclase 1, soluble [6], [8]. Guanylate cyclase 1,soluble activity, in turn, can stimulate cGMP - dependent Protein kinaseG, which abrogates downstream Mitogen activate protein kinases 1 and 3 (ERK1/2 ) phosphorylation by unknown mechanism [8].

Endothelin-1 via EDNRB induces activation of the downstream MAP kinases,mainly ERK1/2. The exact mechanism which leads to ERK1/2 activation isunclear but probably involves several pathways [9].

The first pathway proceeds via a ctivation of the EDNRB by its ligands,leading to t ransformation of the G-protein alpha-q/11 which activatesPhospholipase C beta ( PLC beta) and leads to hydrolysis of Phosphatidylinositol4,5-bisphosphate ( Ptdins(4,5)P2 ) and production of Diacylglycerol ( DAG )and Inositol trisphosphate ( IP3 ) [10]. IP3 leads toCa('2+) cytosol mobilization. Ca('2+) cytosol and DAG can activatesome RAP1A, member of RAS oncogene family ( RAP-1A ) activating factor (e.g., RASguanyl releasing protein 2 ( CALDAG-GEFI )) which transform RAP-1A toactive form. RAP-1A, in turn, activates effector - the v-raf murine sarcoma viraloncogene homolog B1 ( B-Raf ) [9]. DAG, probably, activatesProtein kinase C epsilon ( PKC-epsilon)/ v-Ha-ras Harvey rat sarcoma viraloncogene homolog ( H-Ras)/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 ) pathway [9], [11].

The second pathway involves G-proteins alpha-i family [12] and,possibly, G-proteins beta/gamma [13], which activate cellular oncogenec-Src, which activates protein adaptor Shc/ Growth factor receptor bound2 ( GRB2 )/ Son of sevenless homolog ( SOS)/ H-Ras/c-Raf-1 pathway [12], [14].

Both pathways are merged downstream of B-Raf and c-Raf-1. B-Rafand/or c-Raf-1 phosphorylate and activate Mitogen-activated protein kinase kinases1 and 2 ( MEK1(MAP2K1) and MEK2(MAP2K2) ), which phosphorylate its maindownstream effectors ERK1/2 [9].

ERK1/2 may induce activation of the Ribosomal protein S6 kinase 90kDapolypeptide 2 and 3 ( p90RSK2 and p90RSK3 ). Most probably, ERK1/2activation results in phosphorylation of the ELK1, member of ETS oncogene family (Elk-1 ). In turn, p90RSK s activation results in phosphorylation of cAMPresponsive element binding protein 1 ( CREB1 ) and Activating transcription factor1 ( ATF-1 ). Transcriptional activity of the Elk-1, ATF-1 andCREB1 in this case may induce cellular oncogene v-fos FBJ murine osteosarcomaviral oncogene homolog ( c-Fos ) expression [9].

Proliferation, cell migration and contraction is a physiological consequences of theERK1/2 stimulation [15], [16], [17].