Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
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
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Development Angiotensin activation of ERK


Log In to Post A Comment

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].