Development - Angiotensin activation of ERK

Angiotensin's activation of ERK via transactivation of EGFR

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

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

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

Upon binding with Angiotensin II the Angiotensin II receptor, type-1 is stabilized in its active conformation and stimulates heterotrimeric G proteins. In many Angiotensin II target cells, the Angiotensin II receptor, type-1 interacts primarily with Gq/11 proteins. However, the angiotensin II receptor, type-1 is also coupled with Gi proteins in hepatocytes [4], [5] and in adrenal, pituitary, and renal cells [6], [7]. These G-proteins dissociate into alpha (G-protein alpha-q/11 and G-protein alpha-i family) and beta/gamma (G-protein beta/gamma) subunits [8]. Both subunits take part in the activation of mitogen-activated protein kinase cascade.

G-protein alpha-q/11 and/or G-protein beta/gamma activate the v-Src sarcoma viral oncogene homolog (c-Src) [9]. In addition, G alpha and G beta/gamma subunits act as signal transducers for activation of the Phospholipase C beta (PLC-beta) [10]. PLC-beta activation leads to hydrolysis of Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and formation of Diacylglycerol (DAG) and Inositol trisphosphate (IP3). DAG and IP3 stimulate the Protein kinase C, type delta (PKC-delta) and mobilize intracellular 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)) and activate Pyk2(FAK2)/ c-Src kinase complex [7], [12], [13], [14].

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

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

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

After EGFR phosphorylation, this receptor recruits adaptor proteins (Src homology 2 domain containing transforming protein (Shc) and Growth factor receptor bound 2 (GRB2)) Then, these adaptor proteins are activated by Pyk2(FAK2) and c-Src [9], [13].

Activated Shc and GRB2 recruit Son of sevenless proteins (SOS) for the small GTPase H-Ras. This results in rapid activation of the H-Ras and 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 and MEK2)/ Mitogen-activated protein kinases 1 and 3 (ERK2 and ERK1) kinase cascade [7].

Activation by Angiotensin II leads to nuclear translocation of the ERK1 and ERK2 and further to activation of certain transcription factors (e.g., c-Fos, Elk-1). Thus, ERK signaling cascade participates in a diversity of cellular functions [16].

References:

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