Development - Angiotensin signaling via STATs

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Angiotensin signaling via STAT

Angiotensin II, a major effector peptide of the renin-angiotensin system, is now believed to play a critical role in the pathogenesis of cardiovascular remodeling associated with hypertension, heart failure, and atherosclerosis. [1]

Angiotensin II receptor type1 mediates the major cardiovascular effects of angiotensin II. It relate to guanine nucleotide-binding regulatory protein (G protein)-coupled receptor (GPCR) superfamily. [2] The human angiotensin II receptor type1 is found in liver, lung, adrenal, and adrenocortical adenomas, but not in pheochromocytomas. [3]

Janus kinase/signal transducer and activator of transcription (STAT) pathway play a very important role in transduction of angiotensin II- induced signals. It pathway was initially discovered as a major cytokine signal transduction pathway.

Angiotensin II, after its interaction with the angiotensin II receptor type1, causes directly activation of tyrosine-protein kinase 2 (Jak2) and non-receptor tyrosine-protein kinase (Tyk2), which then activates different STATs (STAT1, STAT2, STAT3, STAT5) under different experimental conditions. [4], [5], [6] Thus, angiotensin II receptor type1 may be able to signal through the intracellular phosphorylation pathways used by cytokine receptors. [4]

It is shown that STAT1 may be regulated by proto-oncogene tyrosine-protein kinase (Fyn) and dual specificity protein phosphatase 1 (MKP-1).

Fyn serves as an angiotensin II-activated docking protein bringing Jak2 and STAT1 together, thereby facilitating Jak2-mediated STAT1 phosphorylation [7] MKP-1 is the phosphatase responsible for STAT1 dephosphorylation and inactivation in VSMCs. [8]

In contrast to the case of angiotensin II-induced tyrosine phosphorylation of STAT1, angiotensin II-induced tyrosine phosphorylation of STAT3 in VSMCs requires proto-oncogene tyrosine-protein kinase (c-Src). In that case, STAT3 is dephosphorylated by PP2A and calcineurin. Serine/threonine protein phosphatase 2A (PP2A) and serine/threonine protein phosphatase calcineurin translocates to the nucleus in response to angiotensin II stimulation of VSMCs and transiently forms a complex with STAT3 just prior to the time during which STAT3 becomes serine-dephosphorylated. [9]

In addition, angiotensin II may activates Janus kinase/STAT pathway via G protein-dependent pathway. [10]

Upon binding with angiotensin II, the angiotensin II receptor type1 is stabilized in its active conformation and stimulates heterotrimeric G proteins (most notably G q/11). These Gq/11-proteins dissociate into alpha (G alpha q/11) and beta/gamma (G beta/gamma) subunits. [11]

G beta/gamma acts as a signal transducer for activation of phospholipase C beta (PLC-beta) by G alpha q/11 [12] PLC-beta activation leads to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and the generation of diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG and IP3 stimulate protein kinase C, type delta (PKC-delta) and mobilise intracellular Ca2+, respectively. [13]

Angiotensin II receptor type1-mediated signals, Ca2+ (via intermediate, presumably - Ca2+/calmodulin-dependent protein kinase II (CaMK II)) [14], [15]) and PKC-delta, activate proline-rich tyrosine kinase 2 (Pyk2). Pyk2 in turn activate preassociated Jak2, (e.g., through recruitment and activation of c-Src). [10]

Activated STATs translocate into the nucleus and regulates gene expression (e.g., c-fos) through binding to specific sequences. In addition, STAT1, STAT2 and interferon-stimulated transcription factor 3, gamma 48kDa (IRF9) may form interferon-stimulated gene factor 3 complex (ISGF3 complex), which initiates the transcription of early growth response genes. [16]

The angiotensin II-induced Janus kinase/STAT pathway plays an essential role in cellular proliferation, the inflammatory response, development of cardiovascular diseases and other. [10]

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. Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE
    Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 1995 May 18;375(6528):247-50
  5. Pan J, Fukuda K, Kodama H, Makino S, Takahashi T, Sano M, Hori S, Ogawa S
    Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. Circulation research 1997 Oct;81(4):611-7
  6. Guo Y, Mascareno E, Siddiqui MA
    Distinct components of Janus kinase/signal transducer and activator of transcription signaling pathway mediate the regulation of systemic and tissue localized renin-angiotensin system. Molecular endocrinology (Baltimore, Md.) 2004 Apr;18(4):1033-41
  7. Chen WS, Kung HJ, Yang WK, Lin W
    Comparative tyrosine-kinase profiles in colorectal cancers: enhanced arg expression in carcinoma as compared with adenoma and normal mucosa. International journal of cancer. Journal international du cancer 1999 Nov 26;83(5):579-84
  8. Venema RC, Venema VJ, Eaton DC, Marrero MB
    Angiotensin II-induced tyrosine phosphorylation of signal transducers and activators of transcription 1 is regulated by Janus-activated kinase 2 and Fyn kinases and mitogen-activated protein kinase phosphatase 1. The Journal of biological chemistry 1998 Nov 13;273(46):30795-800
  9. Liang H, Venema VJ, Wang X, Ju H, Venema RC, Marrero MB
    Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells. The Journal of biological chemistry 1999 Jul 9;274(28):19846-51
  10. Frank GD, Saito S, Motley ED, Sasaki T, Ohba M, Kuroki T, Inagami T, Eguchi S
    Requirement of Ca(2+) and PKCdelta for Janus kinase 2 activation by angiotensin II: involvement of PYK2. Molecular endocrinology (Baltimore, Md.) 2002 Feb;16(2):367-77
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. Schieffer B, Paxton WG, Marrero MB, Bernstein KE
    Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. Hypertension 1996 Mar;27(3 Pt 2):476-80

  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. Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE
    Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 1995 May 18;375(6528):247-50
  5. Pan J, Fukuda K, Kodama H, Makino S, Takahashi T, Sano M, Hori S, Ogawa S
    Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. Circulation research 1997 Oct;81(4):611-7
  6. Guo Y, Mascareno E, Siddiqui MA
    Distinct components of Janus kinase/signal transducer and activator of transcription signaling pathway mediate the regulation of systemic and tissue localized renin-angiotensin system. Molecular endocrinology (Baltimore, Md.) 2004 Apr;18(4):1033-41
  7. Chen WS, Kung HJ, Yang WK, Lin W
    Comparative tyrosine-kinase profiles in colorectal cancers: enhanced arg expression in carcinoma as compared with adenoma and normal mucosa. International journal of cancer. Journal international du cancer 1999 Nov 26;83(5):579-84
  8. Venema RC, Venema VJ, Eaton DC, Marrero MB
    Angiotensin II-induced tyrosine phosphorylation of signal transducers and activators of transcription 1 is regulated by Janus-activated kinase 2 and Fyn kinases and mitogen-activated protein kinase phosphatase 1. The Journal of biological chemistry 1998 Nov 13;273(46):30795-800
  9. Liang H, Venema VJ, Wang X, Ju H, Venema RC, Marrero MB
    Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells. The Journal of biological chemistry 1999 Jul 9;274(28):19846-51
  10. Frank GD, Saito S, Motley ED, Sasaki T, Ohba M, Kuroki T, Inagami T, Eguchi S
    Requirement of Ca(2+) and PKCdelta for Janus kinase 2 activation by angiotensin II: involvement of PYK2. Molecular endocrinology (Baltimore, Md.) 2002 Feb;16(2):367-77
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. Schieffer B, Paxton WG, Marrero MB, Bernstein KE
    Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. Hypertension 1996 Mar;27(3 Pt 2):476-80

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