Development - Angiotensin signaling via PYK2

Angiotensin activation of MAPKs via Pyk2

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 (most notably G q/11). These G-proteins dissociate into alpha (G-protein alpha-q/11) and beta/gamma (G-protein beta/gamma) subunits [4]. Both subunits take part in the activation of mitogen-activated protein kinase cascade.

G-protein alpha-q/11 and G-protein beta/gamma act as signal transducers for activation of the Phospholipase C beta (PLC-beta) [5]. 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 (e.g., PKC-delta and PKC-epsilon) and mobilize intracellular Ca2+, respectively. These effectors are believed to mediate most of the well established acute responses to Angiotensin II, including vasoconstriction, aldosterone biosynthesis and thirst/salt appetite [6].

Angiotensin II receptor, type-1 induces activation of Ca2+/Calmodulin-dependent protein kinase II (CaMK II), PKC-delta and PKC-epsilon. These kinases phosphorylate PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) and activate it [7], [8].

Pyk2(FAK2) is a key tyrosine kinase in the early events of the Angiotensin II signaling. It is a point of split of the Angiotensin II signaling.

Pyk2(FAK2)-dependent phosphorylation and interaction with the adapter molecule protein Crk-associated substrate (p130CAS) lead to their association with the p85 regulatory subunit of Phosphatidylinositol 3-kinase (PI3K reg class 1A (p85)) [9], [10].

This complex formation leads to the activation of PI3K and to regulation of important cell processes, e.g., protein synthesis via regulation of the Eukaryotic initiation factor 4E (eIF4E)/eIF4E-bindind protein (4E-BP) complex [11].

Pyk2(FAK2) is the main mediator responsible for the transmission of Angiotensin II signals to Ras-related C3 botulinum toxin substrate 1 (Rac1) via, e.g, Guanine nucleotide exchange factor VAV-1 [12], [13]). Activated Rac1 stimulates the cascade that involves p21-Activated kinase 1 (PAK1)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1)/ Dual specificity mitogen-activated protein kinase kinase 4 (MEK4)/c-Jun N-terminal kinase (JNK(MAPK8-10)). Tyrosine-protein kinase v-Src sarcoma viral oncogene homolog (c-Src) is also partially involved in Rac1 activation [14].

c-Src in turn may activates Phospholipase C gamma 1 (PLC-gamma 1) that plays the same role as PLC-beta [15].

In additional, Pyk2(FAK2) acts as an upstream regulator of two parallel signaling pathways, ERK and PI3K pathways. The formation of the complex between Src homology 2 domain containing transforming protein (Shc) and Growth factor receptor bound 2 (GRB2) leads to activation of the Son of sevenless proteins (SOS)/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ 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) cascade [9], [16].

Activation by Angiotensin II leads to nuclear translocation of the ERK1, ERK2 and JNK(MAPK8-10) kinases, as well as to activation of transcription factors, e.g. c-Fos, c-Jun, ATF-2, and Elk-1. Many of these factors can form different AP-1 complexes, e.g. ATF-2/c-Jun [14] or c-Jun/c-Fos [17]. Thus, ERK and JNK signaling cascades participate via activation of AP-1 in diverse of cellular functions [18].

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