Development - Angiotensin signaling via PYK2

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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:

  1. Goodfriend TL, Elliott ME, Catt KJ
    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
  3. Takayanagi R, Ohnaka K, Sakai Y, Nakao R, Yanase T, Haji M, Inagami T, Furuta H, Gou DF, Nakamuta M
    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
  4. Luttrell LM, Daaka Y, Lefkowitz RJ
    Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Current opinion in cell biology 1999 Apr;11(2):177-83
  5. Ushio-Fukai M, Griendling KK, Akers M, Lyons PR, Alexander RW
    Temporal dispersion of activation of phospholipase C-beta1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits. The Journal of biological chemistry 1998 Jul 31;273(31):19772-7
  6. Thomas WG, Qian H, Smith NJ
    When 6 is 9: 'uncoupled' AT1 receptors turn signalling on its head. Cellular and molecular life sciences : CMLS 2004 Nov;61(21):2687-94
  7. Ginnan R, Singer HA
    CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle. American journal of physiology. Cell physiology 2002 Apr;282(4):C754-61
  8. Du JQ, Sun CW, Tang JS
    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
  9. Rocic P, Govindarajan G, Sabri A, Lucchesi PA
    A role for PYK2 in regulation of ERK1/2 MAP kinases and PI 3-kinase by ANG II in vascular smooth muscle. American journal of physiology. Cell physiology 2001 Jan;280(1):C90-9
  10. Riggins RB, DeBerry RM, Toosarvandani MD, Bouton AH
    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
  16. Shah BH, Catt KJ
    Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Molecular pharmacology 2002 Feb;61(2):343-51
  17. Hamaguchi A, Kim S, Yano M, Yamanaka S, Iwao H
    Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension. Journal of the American Society of Nephrology : JASN 1998 Mar;9(3):372-80
  18. Berk BC, Corson MA
    Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. Circulation research 1997 May;80(5):607-16

  1. Goodfriend TL, Elliott ME, Catt KJ
    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
  3. Takayanagi R, Ohnaka K, Sakai Y, Nakao R, Yanase T, Haji M, Inagami T, Furuta H, Gou DF, Nakamuta M
    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
  4. Luttrell LM, Daaka Y, Lefkowitz RJ
    Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Current opinion in cell biology 1999 Apr;11(2):177-83
  5. Ushio-Fukai M, Griendling KK, Akers M, Lyons PR, Alexander RW
    Temporal dispersion of activation of phospholipase C-beta1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits. The Journal of biological chemistry 1998 Jul 31;273(31):19772-7
  6. Thomas WG, Qian H, Smith NJ
    When 6 is 9: 'uncoupled' AT1 receptors turn signalling on its head. Cellular and molecular life sciences : CMLS 2004 Nov;61(21):2687-94
  7. Ginnan R, Singer HA
    CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle. American journal of physiology. Cell physiology 2002 Apr;282(4):C754-61
  8. Du JQ, Sun CW, Tang JS
    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
  9. Rocic P, Govindarajan G, Sabri A, Lucchesi PA
    A role for PYK2 in regulation of ERK1/2 MAP kinases and PI 3-kinase by ANG II in vascular smooth muscle. American journal of physiology. Cell physiology 2001 Jan;280(1):C90-9
  10. Riggins RB, DeBerry RM, Toosarvandani MD, Bouton AH
    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
  16. Shah BH, Catt KJ
    Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation. Molecular pharmacology 2002 Feb;61(2):343-51
  17. Hamaguchi A, Kim S, Yano M, Yamanaka S, Iwao H
    Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension. Journal of the American Society of Nephrology : JASN 1998 Mar;9(3):372-80
  18. Berk BC, Corson MA
    Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. Circulation research 1997 May;80(5):607-16

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