Pathway maps

Apoptosis and survival_Anti-apoptotic action of membrane-bound ESR1
Apoptosis and survival_Anti-apoptotic action of membrane-bound ESR1

Object List (links open in MetaCore):

Cytochrome c, eNOS, ASK1 (MAP3K5), PDK (PDPK1), MEK1 (MAP2K1), MEK2 (MAP2K2), PKC-epsilon, ESR1 (membrane), PKC-alpha, Nitric Oxide, Bcl-2,, 17beta-Estradiol, PI3K cat class IA, c-Src, PtdIns(4,5)P2, Erk (MAPK1/3), Ca('2) cytosol, JNK (MAPK8-10), p90RSK1, Ca('2+) extracellular region, BAD, (L)-arginine, c-Raf-1, PtdIns(3,4,5)P3, PI3K reg class IA (p85), L-type Ca(II) channel, alpha 1C subunit, (S)-citrulline, Bax, <extracellular region> Ca('2+) = <cytosol> Ca('2+), , Bcl-XL, AKT(PKB), CREB1, MEK4 (MAP2K4)


Anti-apoptotic action of membrane-bound ESR1

17beta-estradiol exerts an anti-apoptotic effect on a wide variety of tissues that is mediated via activation of membrane bound Estrogen receptor 1 ( ESR1(membrane) ), which activates several anti-apoptotic pathways [1], [2], [3].

Activated ESR1(membrane) binds to and activates Phosphoinositide-3-kinase ( PI3K ) [4], [5]. PI3K via Phosphatidylinositol (3,4,5) trisphosphate ( PtdIns(3,4,5)P3 ) and 3-phosphoinositide dependent protein kinase-1 ( PDK(PDPK1) ) activates V-akt murine thymoma viral oncogene homologs ( AKT(PKB) ) [6]. Upon 17beta-estradiol action, activated AKT(PKB) promotes several anti-apoptotic pathways.

Primarily, AKT(PKB) phosphorylates and activates Nitric oxide synthase 3 ( eNOS ) which catalyzes the synthesis reaction of Nitric oxide [4], [7]. Nitric oxide promotes cell survival by several mechanisms, including inhibition of mitochondrial permeability transition pore opening [8].

AKT(PKB) directly phosphorylates and activates CREB1, which regulates transcription of Bcl-2 [9], [2]. [10]. Also, AKT(PKB) phosphorylates and inhibits BAD, thus preventing its binding and inhibition of Bcl-2 and Bcl-XL [11].

As a result of 17beta-estradiol action AKT(PKB) inhibits Mitogen-activated protein kinase kinase kinase 5 ( ASK1 (MAP3K5) )/ Mitogen-activated protein kinase kinase 4 ( MEK4(MAP2K4) )/ Mitogen-activated protein kinases 8-10 ( JNK (MAPK8-10) cascade preventing inhibition of Bcl-2 and Bcl-XL [12], [13], [14].

Activation of Bcl-2 and Bcl-XL and suppression of Bax under 17beta-estradiol action prevents formation of mitochondrial permeability transition pore, release of Cytochrome C from the mitochondria into the cytoplasm, and activation of caspase cascade [11], [15].

17beta-estradiol can also activate Protein kinases C (PKC) (e.g., PKC-epsilon and/or PKC-alpha ) [16], [17]. This may be realized via PtdIns(3,4,5)P3 [18] and PDK(PDPK1) [19], [20]. PKC-epsilon and/or PKC-alpha phosphorylates voltage-dependent Calcium channel L type alpha 1C subunit ( L-type Ca(II) channel, alpha 1C subunit ) and promotes Ca('2+) transport into the cytosol [16], [21]. Intracellular Ca('2+) rise activates Ca-dependent conventional forms of PKC, possibly PKC-alpha, which activates V-src sarcoma viral oncogene homolog ( c-Src )/ V-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ Mitogen-activated protein kinases 1 and 3 ( Erk(MAPK1/3) ) pathway [22], [23], [24]. Activated Erk(MAPK1/3) phosphorylates and activates Ribosomal protein S6 kinase 90kDa polypeptide 1 ( p90RSK1 ) [25], [26], which activates cAMP responsive element binding protein 1 ( CREB1 ), and that in turn promotes transcription of anti-apoptotic protein B-cell CLL/lymphoma 2 ( Bcl-2 ) [11], [21], [27]. PKC-epsilon activated by 17beta-estradiol action also can directly bind to BCL2-associated X protein ( Bax ) and inhibit its translocation into mitochondria [28].

ESR1 (membrane) also can directly or through G-proteins signaling activate c-Src, which further leads to Erk(MAPK1/3) and p90RSK2 (RPS6KA3) activation. Activated p90RSK1 directly inhibits BCL2-antagonist of cell death ( BAD ) [25], [26].


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