Pathway Map Details

Development_Angiotensin signaling via PYK2



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PKC-epsilon, 3.1.4.11, VAV-1, Ca('2+) endoplasmic reticulum lumen, Rac1, c-Jun, c-Src, p130CAS, PLC-gamma 1, Angiotensin II receptor, type-1, Ca('2) cytosol, PI3K reg class IA, c-Fos, Elk-1, IP3 receptor, ATF-2/c-Jun, Ca('2+) = Ca('2+), PAK1, c-Raf-1, Pyk2(FAK2), IP3, ERK1 (MAPK3), GRB2, MEK4(MAP2K4), MEK1(MAP2K1), MEK2(MAP2K2), MEKK1(MAP3K1), PKC-delta, c-Jun/c-Fos, PLC-beta, H-Ras, SOS, DAG, Calmodulin, ATF-2, Angiotensin II, ERK2 (MAPK1), CaMK II, G-protein beta/gamma, JNK(MAPK8-10), PtdIns(4,5)P2, G-protein alpha-q/11, Shc

Description:

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].

References:

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    Angiotensin receptors and their antagonists. The New England journal of medicine 1996 Jun 20;334(25):1649-54
  2. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE
    Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature 1991 May 16;351(6323):233-6
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    Molecular cloning, sequence analysis and expression of a cDNA encoding human type-1 angiotensin II receptor. Biochemical and biophysical research communications 1992 Mar 16;183(2):910-6
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    Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Current opinion in cell biology 1999 Apr;11(2):177-83
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    Effect of angiotensin II type 1 receptor on delayed rectifier potassium current in catecholaminergic CATH.a cells. Acta pharmacologica Sinica 2004 Sep;25(9):1145-50
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    Src-dependent association of Cas and p85 phosphatidylinositol 3'-kinase in v-crk-transformed cells. Molecular cancer research : MCR 2003 Apr;1(6):428-37
  11. Rocic P, Jo H, Lucchesi PA
    A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle. American journal of physiology. Cell physiology. 2003 Dec;285(6):C1437-44
  12. Okabe S, Fukuda S, Kim YJ, Niki M, Pelus LM, Ohyashiki K, Pandolfi PP, Broxmeyer HE
    Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1. Blood 2005 Jan 15;105(2):474-80
  13. Bubeck Wardenburg J, Pappu R, Bu JY, Mayer B, Chernoff J, Straus D, Chan AC
    Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 1998 Nov;9(5):607-16
  14. Murasawa S, Matsubara H, Mori Y, Masaki H, Tsutsumi Y, Shibasaki Y, Kitabayashi I, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Iba S, Iwasaka T
    Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase. The Journal of biological chemistry 2000 Sep 1;275(35):26856-63
  15. Touyz RM, Berry C
    Recent advances in angiotensin II signaling. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]. 2002 Sep;35(9):1001-15
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