Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Apoptosis and survival Anti-apoptotic action of membrane-bound ESR1

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Apoptosis and survival Anti-apoptotic action of membrane-bound ESR1

 Anti-apoptotic action of membrane-bound ESR1

17beta-estradiol exerts an anti-apoptotic effect on a wide variety of tissuesthat 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 proteinkinase-1 ( PDK(PDPK1) ) activates V-akt murine thymoma viral oncogene homologs (AKT(PKB) ) [6]. Upon 17beta-estradiol action, activatedAKT(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 severalmechanisms, including inhibition of mitochondrial permeability transition pore opening[8].

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

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

Activation of Bcl-2 and Bcl-XL and suppression of Bax under17beta-estradiol action prevents formation of mitochondrial permeabilitytransition 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 maybe realized via PtdIns(3,4,5)P3 [18] and PDK(PDPK1) [19], [20]. PKC-epsilon and/or PKC-alpha phosphorylatesvoltage-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-dependentconventional forms of PKC, possibly PKC-alpha, which activates V-src sarcomaviral oncogene homolog ( c-Src )/ V-raf-1 murine leukemia viral oncogene homolog1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 andMEK2 )/ 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 responsiveelement binding protein 1 ( CREB1 ), and that in turn promotes transcription ofanti-apoptotic protein B-cell CLL/lymphoma 2 ( Bcl-2 ) [11], [21], [27]. PKC-epsilon activated by 17beta-estradiolaction also can directly bind to BCL2-associated X protein ( Bax ) and inhibit itstranslocation into mitochondria [28].

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