Pathway Map Details

Development_Angiotensin activation of ERK

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Object list (links open in MetaCore):, IP3, Ca('2+) endoplasmic reticulum lumen, ERK1 (MAPK3), GRB2, MEK2(MAP2K2), MEK1(MAP2K1), c-Src, PKC-delta, Angiotensin II receptor, type-1, PLC-beta, H-Ras, ADAM12, SOS, Ca('2) cytosol, c-Fos, Elk-1, DAG, Calmodulin, IP3 receptor, Angiotensin II, Ca('2+) = Ca('2+), ERK2 (MAPK1), CaMK II, G-protein beta/gamma, c-Raf-1, HB-EGF, PtdIns(4,5)P2, EGFR, G-protein alpha-q/11, Pyk2(FAK2), G-protein alpha-i family, Shc


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 [12], [13], [7], [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 [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-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].


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