Development - Angiotensin activation of Akt

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Angiotensin's activation of Akt via transactivation EGFR

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].

It has been shown that angiotensin II may stimulate a serine/threonine protein kinase (Akt) through activate of p38 mitogen-activated protein kinase (p38 MAPK) and transactivation of epidermal growth factor receptor (EGFR) in vascular smooth muscle cells [4].

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 [5]. Both subunits take part in this pathway activation Akt.

G alpha q/11 and G beta/gamma act as signal transducers for activation of phospholipase C beta (PLC-beta) [6]. 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) [7]. DAG and IP3 stimulate protein kinase C, type alpha (PKC-alpha) and mobilise intracellular Ca2+, respectively. These effectors are thought to mediate most of the well-established acute responses to angiotensin II, including vasoconstriction, aldosterone biosynthesis and thirst/salt appetite [8].

PI(4,5)P2, Ca2+/calmodulin-dependent protein kinase II (CaMK II) and (PKC-alpha), may activate of cytosolic phospholipase A2, group-IVA (PLA2G4A) [9], [10], [11], [12].

PLA2G4A hydrolyzes phosphatidylcholine (2-arachidonoyl-1-alkyl-sn-glycero-3-phosphocholine) to produce lyso-phosphatidylcholine and arachidonic acid [13], [14], [15].

Further, arachidonic acid is metabolized by some enzymes into hydroxyeicosatetraenoic and/or epoxyeicosatrienoic acids, which may activated p38 MAPK. For example, 12-lipoxygenase (ALOX12) converts arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE) which than converts to 12-hydroxyeicosatetraenoic acid (12-HETE) by glutathione peroxidase 1 (GPX1) and peroxiredoxin 6 (NSGPeroxidase).

It has been shown that 12-HETE activates small GTP binding proteins: cell division cycle 42 (Cdc42) and ras-related C3 botulinum toxin substrate 1 (Rac1) [16], [17] and stimulates mitogen-activated protein kinase kinase kinase 11 (MLK3)/ dual specificity mitogen activated protein kinase kinases (MEK3 and MEK6)/ p38 MAPK pathway [4], [18].

Isoforms p38 MAPKs (alpha, beta, gamma, delta) activate phospholipase D2 (PLD2) and results in 1-acyl-2-arachidonoyl-glycerophosphate production, which stimulates EGFR transactivation [4].

Transactivated EGFR in turn allows to activate phosphatidylinositol 3-kinase (PI3K), which stimulates the conversion of PI(4,5)P2 to phosphatidylinositol (3,4,5) trisphosphate (PI(3,4,5)P3).

PI(3,4,5)P3 binds to the pleckstrin-homology domain of Akt, recruits Akt to the plasma membrane, and exposes Akt to phosphorylation at by 3-phosphoinositide-dependent protein kinase 1 (PDK) [19].

Phosphorylated and activated Akts stimulates several downstream effectors, which regulate cell survival, cell cycle, glucose metabolism, angiogenesis, vasomotor tone, and protein synthesis [20].

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. Li F, Malik KU
    Angiotensin II-induced Akt activation through the epidermal growth factor receptor in vascular smooth muscle cells is mediated by phospholipid metabolites derived by activation of phospholipase D. The Journal of pharmacology and experimental therapeutics 2005 Mar;312(3):1043-54
  5. 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
  6. 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
  7. Rhee SG
    Regulation of phosphoinositide-specific phospholipase C. Annual review of biochemistry 2001;70:281-312
  8. 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
  9. Mosior M, Six DA, Dennis EA
    Group IV cytosolic phospholipase A2 binds with high affinity and specificity to phosphatidylinositol 4,5-bisphosphate resulting in dramatic increases in activity. The Journal of biological chemistry 1998 Jan 23;273(4):2184-91
  10. Li F, Malik KU
    Angiotensin II-induced Akt activation is mediated by metabolites of arachidonic acid generated by CaMKII-stimulated Ca2(+)-dependent phospholipase A2. American journal of physiology. Heart and circulatory physiology 2005 May;288(5):H2306-16
  11. Muthalif MM, Benter IF, Karzoun N, Fatima S, Harper J, Uddin MR, Malik KU
    20-Hydroxyeicosatetraenoic acid mediates calcium/calmodulin-dependent protein kinase II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. Proceedings of the National Academy of Sciences of the United States of America 1998 Oct 13;95(21):12701-6
  12. Xing M, Firestein BL, Shen GH, Insel PA
    Dual role of protein kinase C in the regulation of cPLA2-mediated arachidonic acid release by P2U receptors in MDCK-D1 cells: involvement of MAP kinase-dependent and -independent pathways. The Journal of clinical investigation 1997 Feb 15;99(4):805-14
  13. Niwa Y, Kano T, Taniguchi S, Miyachi Y, Sakane T
    Effect of cyclosporin A on the membrane-associated events in human leukocytes with special reference to the similarity with dexamethasone. Biochemical pharmacology 1986 Mar 15;35(6):947-51
  14. Imai A, Yano K, Kameyama Y, Nozawa Y
    Evidence for predominance of phospholipase A2 in release of arachidonic acid in thrombin-activated platelets: phosphatidylinositol-specific phospholipase C may play a minor role in arachidonate liberation. The Japanese journal of experimental medicine 1982 Apr;52(2):99-105
  15. Kyono K, Hoshi K, Saito A, Tsuiki A, Hoshiai H, Suzuki M
    Effects of phospholipase A2, lysophosphatidyl choline, and fatty acid on the acrosome reaction of human spermatozoa. The Tohoku journal of experimental medicine 1984 Nov;144(3):257-63
  16. Wen Y, Nadler JL, Gonzales N, Scott S, Clauser E, Natarajan R
    Mechanisms of ANG II-induced mitogenic responses: role of 12-lipoxygenase and biphasic MAP kinase. The American journal of physiology 1996 Oct;271(4 Pt 1):C1212-20
  17. Wen Y, Gu J, Knaus UG, Thomas L, Gonzales N, Nadler JL
    Evidence that 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid activates p21-activated kinase. The Biochemical journal 2000 Jul 15;349(Pt 2):481-7
  18. Kalyankrishna S, Malik KU
    Norepinephrine-induced stimulation of p38 mitogen-activated protein kinase is mediated by arachidonic acid metabolites generated by activation of cytosolic phospholipase A(2) in vascular smooth muscle cells. The Journal of pharmacology and experimental therapeutics 2003 Feb;304(2):761-72
  19. Duncan RF, Peterson H, Sevanian A
    Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress. Free radical biology & medicine 2005 Mar 1;38(5):631-43
  20. Shiojima I, Walsh K
    Role of Akt signaling in vascular homeostasis and angiogenesis. Circulation research 2002 Jun 28;90(12):1243-50

  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. Li F, Malik KU
    Angiotensin II-induced Akt activation through the epidermal growth factor receptor in vascular smooth muscle cells is mediated by phospholipid metabolites derived by activation of phospholipase D. The Journal of pharmacology and experimental therapeutics 2005 Mar;312(3):1043-54
  5. 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
  6. 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
  7. Rhee SG
    Regulation of phosphoinositide-specific phospholipase C. Annual review of biochemistry 2001;70:281-312
  8. 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
  9. Mosior M, Six DA, Dennis EA
    Group IV cytosolic phospholipase A2 binds with high affinity and specificity to phosphatidylinositol 4,5-bisphosphate resulting in dramatic increases in activity. The Journal of biological chemistry 1998 Jan 23;273(4):2184-91
  10. Li F, Malik KU
    Angiotensin II-induced Akt activation is mediated by metabolites of arachidonic acid generated by CaMKII-stimulated Ca2(+)-dependent phospholipase A2. American journal of physiology. Heart and circulatory physiology 2005 May;288(5):H2306-16
  11. Muthalif MM, Benter IF, Karzoun N, Fatima S, Harper J, Uddin MR, Malik KU
    20-Hydroxyeicosatetraenoic acid mediates calcium/calmodulin-dependent protein kinase II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. Proceedings of the National Academy of Sciences of the United States of America 1998 Oct 13;95(21):12701-6
  12. Xing M, Firestein BL, Shen GH, Insel PA
    Dual role of protein kinase C in the regulation of cPLA2-mediated arachidonic acid release by P2U receptors in MDCK-D1 cells: involvement of MAP kinase-dependent and -independent pathways. The Journal of clinical investigation 1997 Feb 15;99(4):805-14
  13. Niwa Y, Kano T, Taniguchi S, Miyachi Y, Sakane T
    Effect of cyclosporin A on the membrane-associated events in human leukocytes with special reference to the similarity with dexamethasone. Biochemical pharmacology 1986 Mar 15;35(6):947-51
  14. Imai A, Yano K, Kameyama Y, Nozawa Y
    Evidence for predominance of phospholipase A2 in release of arachidonic acid in thrombin-activated platelets: phosphatidylinositol-specific phospholipase C may play a minor role in arachidonate liberation. The Japanese journal of experimental medicine 1982 Apr;52(2):99-105
  15. Kyono K, Hoshi K, Saito A, Tsuiki A, Hoshiai H, Suzuki M
    Effects of phospholipase A2, lysophosphatidyl choline, and fatty acid on the acrosome reaction of human spermatozoa. The Tohoku journal of experimental medicine 1984 Nov;144(3):257-63
  16. Wen Y, Nadler JL, Gonzales N, Scott S, Clauser E, Natarajan R
    Mechanisms of ANG II-induced mitogenic responses: role of 12-lipoxygenase and biphasic MAP kinase. The American journal of physiology 1996 Oct;271(4 Pt 1):C1212-20
  17. Wen Y, Gu J, Knaus UG, Thomas L, Gonzales N, Nadler JL
    Evidence that 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid activates p21-activated kinase. The Biochemical journal 2000 Jul 15;349(Pt 2):481-7
  18. Kalyankrishna S, Malik KU
    Norepinephrine-induced stimulation of p38 mitogen-activated protein kinase is mediated by arachidonic acid metabolites generated by activation of cytosolic phospholipase A(2) in vascular smooth muscle cells. The Journal of pharmacology and experimental therapeutics 2003 Feb;304(2):761-72
  19. Duncan RF, Peterson H, Sevanian A
    Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress. Free radical biology & medicine 2005 Mar 1;38(5):631-43
  20. Shiojima I, Walsh K
    Role of Akt signaling in vascular homeostasis and angiogenesis. Circulation research 2002 Jun 28;90(12):1243-50

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