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Development Angiotensin activation of ERK

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Development Angiotensin activation of ERK

Angiotensin's activation of ERK via transactivation ofEGFR

Angiotensin II, a major effector peptide of the renin-angiotensin system, isbelieved to play a critical role in the pathogenesis of cardiovascular remodelingassociated with hypertension, heart failure, and atherosclerosis. [1]

Angiotensin II receptor, type-1 mediates major cardiovascular effects ofAngiotensin II. It belongs to the guanine nucleotide-binding regulatory protein (G protein)-coupled receptor (GPCR) superfamily. [2] Human Angiotensin IIreceptor, type-1 is found in liver, lung, adrenal, and adrenocortical adenomas [3].

In general terms, the mechanisms used by GPCRs to stimulate mitogen-activated proteinkinases (MAPKs) fall into one of several broad categories. One of the importantmechanisms involves the cross-talk between GPCRs and classical receptor tyrosine kinase,e.g., Epidermal growth factor receptor ( EGFR ). This process is calledtransactivation.

Upon binding with Angiotensin II the Angiotensin II receptor, type-1 isstabilized in its active conformation and stimulates heterotrimeric G proteins. In manyAngiotensin II target cells, the Angiotensin II receptor, type-1 interactsprimarily with Gq/11 proteins. However, the angiotensin II receptor, type-1 isalso coupled with Gi proteins in hepatocytes [4], [5] and inadrenal, pituitary, and renal cells [6], [7]. These G-proteinsdissociate into alpha ( G-protein alpha-q/11 and G-protein alpha-i family )and beta/gamma ( G-protein beta/gamma ) subunits [8]. Both subunitstake part in the activation of mitogen-activated protein kinase cascade.

G-protein alpha-q/11 and/or G-protein beta/gamma activate the v-Srcsarcoma viral oncogene homolog ( c-Src ) [9]. In addition, G alphaand G beta/gamma subunits act as signal transducers for activation of the Phospholipase Cbeta ( PLC-beta ) [10]. PLC-beta activation leads to hydrolysisof Phosphatidylinositol 4,5-bisphosphate ( PtdIns(4,5)P2 ) and formation ofDiacylglycerol ( DAG ) and Inositol trisphosphate ( IP3 ). DAG andIP3 stimulate the Protein kinase C, type delta ( PKC-delta ) and mobilizeintracellular Ca2+, respectively [11].

Angiotensin II receptor, type-1 induces activation of Ca2+/Calmodulin -dependent protein kinase II ( CaMK II ) and PKC-delta.Both kinases phosphorylate PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) ) andactivate Pyk2(FAK2)/ c-Src kinase complex [12], [13], [7], [14].

Activated c-Src is a key intermediate in transactivation of the EGFRthrough metalloproteases (ADAMs, e.g. ADAM12 )/ Heparin-binding EGF-like growthfactor ( HB-EGF ) pathway.

Like other members of the EGF family, HB-EGF is synthesized as amembrane-anchored insoluble form and then processed to a bioactive soluble form. Thisprocess is called ectodomain shedding [15].

HB-EGF activates EGFR and stimulates EGFR phosphorylation byc-Src [9].

After EGFR phosphorylation, this receptor recruits adaptor proteins (Srchomology 2 domain containing transforming protein ( Shc ) and Growth factorreceptor bound 2 ( GRB2 )) Then, these adaptor proteins are activated byPyk2(FAK2) and c-Src [13], [9].

Activated Shc and GRB2 recruit Son of sevenless proteins ( SOS )for the small GTPase H-Ras. This results in rapid activation of the H-Rasand subsequentl activation of the v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 andMEK2 )/ Mitogen-activated protein kinases 1 and 3 ( ERK2 and ERK1 ) kinasecascade [7].

Activation by Angiotensin II leads to nuclear translocation of the ERK1and ERK2 and further to activation of certain transcription factors (e.g.,c-Fos, Elk-1). Thus, ERK signaling cascade participates in a diversity ofcellular functions [16].