Pathway Map Details

Development_EDNRB signaling

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None, Elk-1, ERK1/2, PtdIns(3,4,5)P3, 2 (L)-arginine + 3 NAD(P)H + 4 O(,2) = 4 H(,2)O + 3 NAD(P)('+) + 2 (S)-citrulline + 2 NO, Caveolin-1, Endothelin-3, Cyclic GMP cytosol, G-proteins beta/gamma, PKC-epsilon, GTP, Ca('2+) = Ca('2+), PI3K reg class IB (p101), DAG, Ca('2+) endoplasmic reticulum, Ca('2) cytosol, Protein kinase G, PLC-beta, ATF-1, PI3K cat class IB (p110-gamma), eNOS, Nitric Oxide, MEK2(MAP2K2), EDNRB, L-arginine, Endothelin-1, (S)-citrulline, PtdIns(4,5)P2, None, H(,2)O + 1-(1,2-diacyl-glycerol 3-phospho)-inositol 4,5-bisphosphate = 1,2-diacyl-glycerol + inositol 1,4,5-trisphosphate, p90RSK3(RPS6KA2), SOS, IP3, B-Raf, c-Src, CREB1, CALDAG-GEFI, RAP-1A, G-protein alpha-q/11, IP3 receptor, c-Raf-1, H-Ras, Shc, Guanylate cyclase 1, soluble, MEK1(MAP2K1), G-protein alpha-i family, GRB2, AKT(PKB), c-Fos, p90RSK2(RPS6KA3)


EDNRB signaling

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

Scaffolding Caveolin 1, caveolae protein, 22kDa ( Caveolin-1 ) interacts with EDNRB. EDNRB bound to Caveolin-1 is targeted to caveolae. Upon Endothelin-1 stimulation, EDNRB dissociates from Caveolin-1 and exits from the caveolae. Caveolae localization of EDNRB is one of the mechanisms to 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 includes the following steps. Endothelin - stimulated ENDRB activates G-protein beta/gamma dissociation from complex with G-protein alpha-i family. G-protein beta/gamma activates Phosphatidylinositol 3 kinase (PI3K) ( most probably, Phosphoinositide-3-kinase, regulatory subunit 5 ( PI3K reg class IB (p101) ) and Phosphoinositide-3-kinase, catalytic, gamma polypeptide ( PI3K cat class IB (p110-gamma) ), which products of PtdIns(3,4,5)P3 from PtdIns(4,5)P2. PtdIns(4,5)P2, in turn, recruits v-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), which activates eNOS by phosphorylation and thus enhances Nitric Oxide production. Enhanced Nitric oxide production during EDNRB stimulation results in smooth muscle and vascular relaxation [7]. Nitric Oxide, in turn, enhances intracellular concentration of cGMP, most likely by activation of the Guanylate cyclase 1, soluble [6], [8]. Guanylate cyclase 1, soluble activity, in turn, can stimulate cGMP - dependent Protein kinase G, 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 is unclear 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 activates Phospholipase C beta ( PLC beta) and leads to hydrolysis of Phosphatidylinositol 4,5-bisphosphate ( Ptdins(4,5)P2 ) and production of Diacylglycerol ( DAG ) and Inositol trisphosphate ( IP3 ) [10]. IP3 leads to Ca('2+) cytosol mobilization. Ca('2+) cytosol and DAG can activate some RAP1A, member of RAS oncogene family ( RAP-1A ) activating factor (e.g., RAS guanyl releasing protein 2 ( CALDAG-GEFI )) which transform RAP-1A to active form. RAP-1A, in turn, activates effector - the v-raf murine sarcoma viral oncogene homolog B1 ( B-Raf ) [9]. DAG, probably, activates Protein kinase C epsilon ( PKC-epsilon)/ v-Ha-ras Harvey rat sarcoma viral oncogene 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 oncogene c-Src, which activates protein adaptor Shc/ Growth factor receptor bound 2 ( 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-Raf and/or c-Raf-1 phosphorylate and activate Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) and MEK2(MAP2K2) ), which phosphorylate its main downstream effectors ERK1/2 [9].

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

Proliferation, cell migration and contraction is a physiological consequences of the ERK1/2 stimulation [15], [16], [17].


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