Opportunities to target specific contractile abnormalities with smooth muscle protein kinase inhibitors

Pharmaceuticals

Volumn 3, Issue 6, 2010, Pages 1739-1760

  Ulke Lemée, Annegret ^a   MacDonald, Justin A ^a  

^a UNIVERSITY OF CALGARY   (Canada)

Author keywords

Calcium sensitization; CPI 17; Integrin linked kinase; Myosin light chain diphosphorylation; Myosin phosphatase; MYPT1; Rho associated kinase; Zipper interacting protein kinase

Indexed keywords

CALCIUM ION; DEATH ASSOCIATED PROTEIN KINASE; FASUDIL; INTEGRIN LINKED KINASE; RHO KINASE INHIBITOR; UNCLASSIFIED DRUG; ZIPPER INTERACTING PROTEIN KINASE;

ALZHEIMER DISEASE; BRAIN VASOSPASM; CALCIUM CELL LEVEL; CLINICAL TRIAL; DEMENTIA; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVITY; HUMAN; INTESTINE MUSCLE; NONHUMAN; PROTEIN DEPHOSPHORYLATION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; SMOOTH MUSCLE CONTRACTION; STABLE ANGINA PECTORIS; VASODILATATION;

EID: 77954895525     PISSN: None     EISSN: 14248247     Source Type: Journal    
DOI: 10.3390/ph3061739     Document Type: Review

References (98)

1. 2+ sensitivity of smooth muscle and nonmuscle myosin II: Modulated by G proteins, kinases, and myosin phosphatase. Physiol. Rev. 2003, 83, 1325-1358.
2. Gerthoffer, W.T. Signal-transduction pathways that regulate visceral smooth muscle function. III. Coupling of muscarinic receptors to signaling kinases and effector proteins in gastrointestinal smooth muscles. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G849-G853.
3. Murthy, K.S. Signaling for contraction and relaxation in smooth muscle of the gut. Annu. Rev. Physiol. 2006, 68, 345-374.
4. Kim, H.R.; Appel, S.; Vetterkind, S.; Gangopadhyay, S.S.; Morgan, K.G. Smooth muscle signalling pathways in health and disease. J. Cell. Mol. Med. 2008, 12, 2165-2180.
5. Chong, D.Y.; Michel, T. Pharmacology of vascular tone. In Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy; Golan, D.E., Tashjian, A.H., Jr., Armstrong, E.J., Armstrong A.W., Eds.; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2008; pp. 367-386.
6. Matsumura, F.; Hartshorne, D.J. Myosin phosphatase target subunit: Many roles in cell function. Biochem. Biophys. Res. Commun. 2008, 369, 149-156.
7. Bradley, A.B.; Morgan, K.G. Alterations in cytoplasmic calcium sensitivity during porcine coronary artery contractions as detected by aequorin. J. Physiol. 1987, 385, 437-448.
8. 2+-independent myosin diphosphorylation and contraction of vascular smooth muscle. Biochem. J. 2005, 392, 641-648.
9. Harnett, K.M.; Biancani, P. Calcium-dependent and calcium-independent contractions in smooth muscles. Am. J. Med. 2003, 115, 24-30.
10. Ikebe, M.; Hartshorne, D.J. Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase. J. Biol. Chem. 1985, 260, 10027-10031.
11. Murata-Hori, M.; Suizu, F.; Iwasaki, T.; Kikuchi, A.; Hosoya, H. ZIP kinase identified as a novel myosin regulatory light chain kinase in HeLa cells. FEBS Lett. 1999, 451, 81-84.
12. Niiro, N.; Ikebe, M. Zipper-interacting protein kinase induces Ca(2+)-free smooth muscle contraction via myosin light chain phosphorylation. J. Biol. Chem. 2001, 276, 29567-29574.
13. Borman, M.A.; MacDonald, J.A.; Haystead, T.A. Staurosporine inhibition of zipper-interacting protein kinase contractile effects in gastrointestinal smooth muscle. Biochem. Cell Biol. 2007, 85, 111-120.
14. 2+ sensitization of the contractile apparatus in vascular smooth muscle. J. Pharmacol. Sci. 2007, 104, 109-115.
15. Seto, M.; Yano, K.; Sasaki, Y.; Azuma, H. Intimal hyperplasia enhances myosin phosphorylation in rabbit carotid artery. Exp. Mol. Pathol. 1993, 58, 1-13.
16. Bulter, W.E.; Peterson, J.W.; Zervas, N.T.; Morgan, K.G. Intracellular calcium, myosin light chain phosphorylation, and contractile force in experimental cerebral vasospasm. Neurosurgery 1996, 38, 781-788.
17. Harada, T.; Seto, M.; Sasaki, Y.; London, S.; Luo, Z.; Mayberg, M. The time course of myosin light-chain phosphorylation in blood-induced vasospasm. Neurosurgery 1995, 36, 1178-1183.
18. Katsumata, N.; Shimokawa, H.; Seto, M.; Kozai, T.; Yamawaki, T.; Kuwata, K.; Egashira, K.; Ikegaki, I.; Asano, T.; Sasaki, Y.; Takeshita, A. Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta. Circulation 1997, 96, 4357-4363.
19. Hosseini, J.M.; Goldhill, J.M.; Bossone, C.; Pineiro-Carrero, V.; Shea-Donohue, T. Progressive alterations in circular smooth muscle contractility in TNBS-induced colitis in rats. Neurogastroenterol. Motil. 1999, 11, 347-356.
20. Ozaki, H.; Hori, M.; Kinoshita, K.; Ohama, T. Intestinal dysmotility in inflammatory bowel disease: Mechanisms of the reduced activity of smooth muscle contraction. Inflammopharmacology 2005, 13, 103-111.
21. Vrees, M.D.; Pricolo, V.E.; Potenti, F.M.; Cao, W. Abnormal motility in patients with ulcerative colitis: The role of inflammatory cytokines. Arch. Surg. 2002, 137, 439-446.
22. Akiho, H.; Deng, Y.; Blennerhassett, P.; Kanbayashi, H.; Collins, S.M. Mechanisms underlying the maintenance of muscle hypercontractility in a model of postinfective gut dysfunction. Gastroenterology 2005, 129, 131-141.
23. Cook, T.A.; Brading, A.F.; Mortensen, N.J. Abnormal contractile properties of rectal smooth muscle in chronic ulcerative colitis. Aliment. Pharmacol. Ther. 2000, 14, 1287-1294.
24. Olson, M.F. Applications for ROCK kinase inhibition. Curr. Opin. Cell Biol. 2008, 20, 242-248.
25. Schmandke, A.; Schmandke, A.; Strittmatter, S.M. ROCK and Rho: Biochemistry and neuronal functions of Rho-associated protein kinases. Neuroscientist 2007, 13, 454-469.
26. Lowery, D.M.; Clauser, K.R.; Hjerrild, M.; Lim, D.; Alexander, J.; Kishi, K.; Ong, S.E.; Gammeltoft, S.; Carr, S.A.; Yaffe, M.B. Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. EMBO J. 2007, 26, 2262-2273.
27. Kawano, Y.; Fukata, Y.; Oshiro, N.; Amano, M.; Nakamura, T.; Ito, M.; Matsumura, F.; Inagaki, M.; Kaibuchi, K. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J. Cell Biol. 1999, 147, 1023-1038.
28. Kimura, K.; Ito, M.; Amano, M.; Chihara, K.; Fukata, Y.; Nakafuku, M.; Yamamori, B.; Feng, J.; Nakano, T.; Okawa, K.; Iwamatsu, A.; Kaibuchi, K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996, 273, 245-248.
29. Amano, M.; Ito, M.; Kimura, K.; Fukata, Y.; Chihara, K.; Nakano, T.; Matsuura, Y.; Kaibuchi, K. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 1996, 271, 20246-20249.
30. Eto M.; Wong, L.; Yazawa, M.; Brautigan, D.L. Inhibition of myosin/moesin phosphatase by expression of the phosphoinhibitor protein CPI-17 alters microfilament organization and retards cell spreading. Cell Motil. Cytoskeleton 2000, 46, 222-234.
31. Doggrell, S.A. Rho-kinase inhibitors show promise in pulmonary hypertension. Expert Opin. Investig. Drugs 2005, 14, 1157-1159.
32. Huentelman, M.J.; Stephan, D.A.; Talboom, J.; Corneveaux, J.J.; Reiman, D.M.; Gerber, J.D.; Barnes, C.A.; Alexander, G.E.; Reiman, E.M.; Bimonte-Nelson, H.A. Peripheral delivery of a ROCK inhibitor improves learning and working memory. Behav. Neurosci. 2009, 123, 218-223.
33. Breitenlechner, C.; Gassel, M.; Hidaka, H.; Kinzel, V.; Huber, R.; Engh, R.A.; Bossemeyer, D. Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity. Structure 2003, 11, 1595-1607.
34. Yamaguchi, H.; Kasa, M.; Amano, M.; Kaibuchi, K.; Hakoshima, T. Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Structure 2006, 14, 589-600.
35. Takayasu, M.; Suzuki, Y.; Shibuya, M.; Asano, T.; Kanamori, M.; Okada, T.; Kageyama, N.; Hidaka, H. The effects of HA compound calcium antagonists on delayed cerebral vasospasm in dogs. J. Neurosurg. 1986, 65, 80-85.
36. Vicari, R.M.; Chaitman, B.; Keefe, D.; Smith, W.B.; Chrysant, S.G.; Tonkon, M.J.; Bittar, N.; Weiss, R.J.; Morales-Ballejo, H.; Thadani, U. Efficacy and safety of fasudil in patients with stable angina: A double-blind, placebo-controlled, phase 2 trial. J. Am. Coll. Cardiol. 2005, 46, 1803-1811.
37. Shibuya, M.; Hirai, S.; Seto, M.; Satoh, S.; Ohtomo, E. Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial. J. Neurol. Sci. 2005, 238, 31-39.
38. Nohria, A.; Grunert, M.E.; Rikitake, Y.; Noma, K.; Prsic, A.; Ganz, P.; Liao, J.K.; Creager, M.A. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ. Res. 2006, 99, 1426-1432.
39. Noma, K.; Higashi, Y.; Jitsuiki, D.; Hara, K.; Kimura, M.; Nakagawa, K.; Goto, C.; Oshima, T.; Yoshizumi, M.; Chayama, K. Smoking activates rho-kinase in smooth muscle cells of forearm vasculature in humans. Hypertension 2003, 41, 1102-1105.
40. Noma, K.; Goto, C.; Nishioka, K.; Jitsuiki, D.; Umemura, T.; Ueda, K.; Kimura, M.; Nakagawa, K.; Oshima, T.; Chayama, K.; et al. Roles of rho-associated kinase and oxidative stress in the pathogenesis of aortic stiffness. J. Am. Coll. Cardiol. 2007, 49, 698-705.
41. Nagata, K.; Kondoh, Y.; Satoh, Y.; Watahiki, Y.; Yokoyama, E.; Yuya, H.; Hirata, Y.; Shishido, F.; Hatazawa, J.; Kanno, I.; et al. Effects of fasudil hydrochloride on cerebral blood flow in patients with chronic cerebral infarction. Clin. Neuropharmacol. 1993, 16, 501-510.
42. Inokuchi, K.; Ito, A.; Fukumoto, Y.; Matoba, T.; Shiose, A.; Nishida, T.; Masuda, M.; Morita, S.; Shimokawa, H. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. J. Cardiovasc. Pharmacol. 2004, 44, 275-277.
43. Mohri, M.; Shimokawa, H.; Hirakawa, Y.; Masumoto, A.; Takeshita, A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J. Am. Coll. Cardiol. 2003, 41, 15-19.
44. Eldawoody, H.; Shimizu, H.; Kimura, N.; Saito, A.; Nakayama, T.; Takahashi, A.; Tominaga, T. Fasudil, a Rho-kinase inhibitor, attenuates induction and progression of cerebral aneurysms: Experimental study in rats using vascular corrosion casts. Neurosci. Lett. 2010, 470, 76-80.
45. Wang, Y.X.; Martin-McNulty, B.; da Cunha, V.; Vincelette, J.; Lu, X.; Feng, Q.; Halks-Miller, M.; Mahmoudi, M.; Schroeder, M.; Subramanyam, B.; et al. Fasudil, a Rho-kinase inhibitor, attenuates angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice by inhibiting apoptosis and proteolysis. Circulation 2005, 111, 2219-2226.
46. Fukunaga, T.; Ikesugi, K.; Nishio, M.; Sugimoto, M.; Sasoh, M.; Hidaka, H.; Uji, Y. The effect of the Rho-associated protein kinase inhibitor, HA-1077, in the rabbit ocular hypertension model induced by water loading. Curr. Eye. Res. 2009, 34, 42-47.
47. Kishi, T.; Hirooka, Y.; Masumoto, A.; Ito, K.; Kimura, Y.; Inokuchi, K.; Tagawa, T.; Shimokawa, H.; Takeshita, A.; Sunagawa, K. Rho-kinase inhibitor improves increased vascular resistance and impaired vasodilation of the forearm in patients with heart failure. Circulation 2005, 111, 2741-2747.
48. Bussemaker, E.; Herbrig, K.; Pistrosch, F.; Palm, C.; Passauer, J. Role of rho-kinase in the regulation of vascular tone in hypertensive renal transplant recipients. Atherosclerosis 2009, 207, 567-572.
49. Masumoto, A.; Hirooka, Y.; Shimokawa, H.; Hironaga, K.; Setoguchi, S.; Takeshita, A. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension 2001, 38, 1307-1310.
50. Sasaki, Y.; Suzuki, M.; Hidaka, H. The novel and specific Rho-kinase inhibitor (S)-(+)-2-methyl- 1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinaseinvolved pathway. Pharmacol. Ther. 2002, 93, 225-232.
51. Nichols, R.; Dzamko, N.; Hutti, J.; Cantley, L.; Deak, M.; Moran, J.; Bamborough, P.; Reith, A.; Alessi, D. Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. Biochem. J. 2009, 23, 47-60.
52. Lohn, M.; Plettenburg, O.; Ivashchenko, Y.; Kannt, A.; Hofmeister, A.; Kadereit, D.; Schaefer, M.; Linz, W.; Kohlmann, M.; Herbert, J.M.; et al. Pharmacological characterization of SAR407899, a novel Rho-kinase inhibitor. Hypertension 2009, 54, 676-683.
53. Dhaliwal, J.S.; Badejo, A.M., Jr.; Casey, D.B.; Murthy, S.N.; Kadowitz, P.J. Analysis of pulmonary vasodilator responses to SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1- ethyl-1H-imidazo(4,5-c)pyridin- 2-yl)-1,2,5-oxadiazol-3-amine], a novel aminofurazan-based Rho kinase inhibitor. J. Pharmacol. Exp. Ther. 2009, 330, 334-341.
54. 2+ sensitization in rat ileal longitudinal smooth muscle. Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 293, G699-G710.
55. Kim, N.; Cao, W.; Song, I.S.; Kim, C.Y.; Harnett, K.M.; Cheng, L.; Walsh, M.P.; Biancani, P. Distinct kinases are involved in contraction of cat esophageal and lower esophageal sphincter smooth muscles. Am. J. Physiol. Cell Physiol. 2004, 287, C384-C394.
56. Bialik, S.; Kimchi, A. The death-associated protein kinases: structure, function, and beyond. Annu. Rev. Biochem. 2006, 75, 189-210.
57. Ihara, E.; MacDonald, J.A. The regulation of smooth muscle contractility by zipper-interacting protein kinase. Can. J. Physiol. Pharmacol. 2007, 85, 79-87.
58. Haystead, T. A. ZIP kinase, a key regulator of myosin protein phosphatase 1. Cell Signal. 2005, 17, 1313-1322.
59. Komatsu, S.; Ikebe, M. ZIP kinase is responsible for the phosphorylation of myosin II and necessary for cell motility in mammalian fibroblasts. J. Cell Biol. 2004, 165, 243-254.
60. 2+ sensitization via myosin phosphatase inhibition. J. Biol. Chem. 2002, 277, 23441-23446.
61. MacDonald, J.A.; Borman, M.A.; Muranyi, A.; Somlyo, A.V.; Hartshorne, D.J.; Haystead, T.A. Identification of the endogenous smooth muscle myosin phosphatase-associated kinase. Proc. Natl. Acad. Sci. USA 2001, 98, 2419-2424.
62. Kawai, T.; Matsumoto, M.; Takeda, K.; Sanjo, H.; Akira, S. ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. Mol. Cell Biol. 1998, 18, 1642-1651.
63. Kogel, D.; Plottner, O.; Landsberg, G.; Christian, S.; Scheidtmann, K.H. Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones. Oncogene 1998, 17, 2645-2654.
64. Endo, A.; Surks, H.K.; Mochizuki, S.; Mochizuki, N.; Mendelsohn, M.E. Identification and characterization of zipper-interacting protein kinase as the unique vascular smooth muscle myosin phosphatase-associated kinase. J. Biol. Chem. 2004, 279, 42055-42061.
65. MacDonald, J.A.; Eto, M.; Borman, M.A.; Brautigan, D.L.; Haystead, T.A. Dual Ser and Thr phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by MYPT-associated kinase. FEBS Lett. 2001, 493, 91-94.
66. Ihara, E.; Edwards, E.; Borman, M.A.; Wilson, D.P.; Walsh, M.P.; MacDonald, J.A. Inhibition of zipper-interacting protein kinase function in smooth muscle by a myosin light chain kinase pseudosubstrate peptide. Am. J. Physiol. Cell Physiol. 2007, 292, C1951-C1959.
67. 2+-independent contraction of longitudinal ileal smooth muscle is potentiated by a zipperinteracting protein kinase pseudosubstrate peptide. Am. J. Physiol. Gastrointest. Liver Physiol. 2009, 297, G361-G370.
68. Filippakopoulos, P.; Rellos, P.; Eswaran, J.; Fedorov, O.; G., B.; Niesen, F.; Bracher, F.; Huber, K.; Pike, A.C.W.; Roos, A.; Von Delft, F.; et al. Crystal structure of human death associated protein kinase 3 (Dapk3) in complex with a beta-carboline ligand. PDB Deposition 2009, 3BHY.
69. Shohat, G.; Spivak-Kroizman, T.; Cohen, O.; Bialik, S.; Shani, G.; Berrisi, H.; Eisenstein, M.; Kimchi, A. The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism. J. Biol. Chem. 2001, 276, 47460-47467.
70. Shani, G.; Henis-Korenblit, S.; Jona, G.; Gileadi, O.; Eisenstein, M.; Ziv, T.; Admon, A.; Kimchi, A. Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. EMBO J. 2001, 20, 1099-1113.
71. 2+ desensitization. Mol. Cell. Biochem. 1993, 127, 229-237.
72. Sato, N.; Kamada, N.; Muromoto, R.; Kawai, T.; Sugiyama, K.; Watanabe, T.; Imoto, S.; Sekine, Y.; Ohbayashi, N.; Ishida, M.; et al. Phosphorylation of threonine-265 in Zipper-interacting protein kinase plays an important role in its activity and is induced by IL-6 family cytokines. Immunol. Lett. 2006, 103, 127-134.
73. Mukhopadhyay, R.; Ray, P.S.; Arif, A.; Brady, A.K.; Kinter, M.; Fox, P.L. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol. Cell 2008, 32, 371-382.
74. Graves, P.R.; Winkfield, K.M.; Haystead, T.A. Regulation of zipper-interacting protein kinase activity in vitro and in vivo by multisite phosphorylation. J. Biol. Chem. 2005, 280, 9363-9374.
75. Shani, G.; Marash, L.; Gozuacik, D.; Bialik, S.; Teitelbaum, L.; Shohat, G.; Kimchi, A. Deathassociated protein kinase phosphorylates ZIP kinase, forming a unique kinase hierarchy to activate its cell death functions. Mol. Cell Biol. 2004, 24, 8611-8626.
76. Ohbayashi, N.; Okada, K.; Kawakami, S.; Togi, S.; Sato, N.; Ikeda, O.; Kamitani, S.; Muromoto, R.; Sekine, Y.; Kawai, T.; et al. Physical and functional interactions between ZIP kinase and UbcH5. Biochem. Biophys. Res. Commun. 2008, 372, 708-712.
77. Okamoto, M.; Takayama, K.; Shimizu, T.; Ishida, K.; Takahashi, O.; Furuya, T. Identification of death-associated protein kinases inhibitors using structure-based virtual screening. J. Med. Chem. 2009, 52, 7323-7327.
78. Okamoto, M.; Takayama, K.; Shimizu, T.; Muroya, A.; Furuya, T. Structure-activity relationship of novel DAPK inhibitors identified by structure-based virtual screening. Bioorg. Med. Chem. 2010, 18, 2728-2734.
79. Kaidanovich-Beilin, O.; Eldar-Finkelman, H. Peptides targeting protein kinases: Strategies and implications. Physiology 2006, 21, 411-418.
80. Shiga, K.; Takayama, K.; Futaki, S.; Hutti, J.E.; Cantley, L.C.; Ueki, K.; Ono, Y.; Mukai, H. Development of an intracellularly acting inhibitory peptide selective for PKN. Biochem. J. 2010, 425, 445-543.
81. Kemp, B.E.; Parker, M.W.; Hu, S.; Tiganis, T.; House, C. Substrate and pseudosubstrate interactions with protein kinases: Determinants of specificity. Trends Biochem. Sci. 1994, 19, 440-444.
82. Hannigan, G.E.; Leung-Hagesteijn, C.; Fitz-Gibbon, L.; Coppolino, M.G.; Radeva, G.; Filmus, J.; Bell, J.C.; Dedhar, S. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 1996, 379, 91-96.
83. 2+-independent smooth muscle contraction-A novel function for integrin-linked kinase. J. Biol. Chem. 2001, 276, 16365-16373.
84. McDonald, P.C.; Fielding, A.B.; Dedhar, S. Integrin-linked kinase-essential roles in physiology and cancer biology. J. Cell Sci. 2008, 121, 3121-3132.
85. Ho, B.; Bendeck, M.P. Integrin linked kinase (ILK) expression and function in vascular smooth muscle cells. Cell Adh. Migr. 2009, 3, 174-176.
86. Lal, H.; Verma, S.K.; Foster, D.M.; Golden, H.B.; Reneau, J.C.; Watson, L.E.; Singh, H.; Dostal, D.E. Integrins and proximal signaling mechanisms in cardiovascular disease. Front Biosci. 2009, 14, 2307-2334.
87. Hannigan, G.; Troussard, A.A.; Dedhar, S. Integrin-linked kinase: A cancer therapeutic target unique among its ILK. Nat. Rev. Cancer 2005, 5, 51-63.
88. Boudeau, J.; Miranda-Saavedra, D.; Barton, G.J.; Alessi, D.R. Emerging roles of pseudokinases. Trends Cell Biol. 2006, 16, 443-452.
89. Fukuda, K.; Gupta, S.; Chen, K.; Wu, C.; Qin, J. The pseudoactive site of ILK is essential for its binding to alpha-Parvin and localization to focal adhesions. Mol. Cell 2009, 36, 819-830.
90. Yau, C.Y.F.; Wheeler, J.J.; Sutton, K.L.; Hedley, D.W. Inhibition of integrin-linked kinase by a selective small molecule inhibitor, QLT0254, inhibits the PI3K/PKB/mTOR, Stat3, and FKHR pathways and tumor growth, and enhances Gemcitabine-induced apoptosis in human orthotopic primary pancreatic cancer xenografts. Cancer Res. 2005, 65, 1497-1504.
91. Persad, S.; Attwell, S.; Gray, V.; Mawji, N.; Deng, J.T.; Leung, D.; Yan, J.; Sanghera, J.; Walsh, M.P.; Dedhar, S. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrinlinked kinase: Critical roles for kinase activity and amino acids arginine 211 and serine 343. J. Biol. Chem. 2001, 276, 27462-27469.
92. Muranyi, A.; MacDonald, J.A.; Deng, J.T.; Wilson, D.P.; Haystead, T.A.; Walsh, M.P.; Erdodi, F.; Kiss, E.; Wu, Y.; Hartshorne, D.J. Phosphorylation of the myosin phosphatase target subunit by integrin-linked kinase. Biochem. J. 2002, 366, 211-216.
93. Deng, J.T.; Sutherland, C.; Brautigan, D.L.; Eto, M.; Walsh, M.P. Phosphorylation of the myosin phosphatase inhibitors, CPI-17 and PHI-1, by integrin-linked kinase. Biochem. J. 2002, 367, 517-524.
94. Persad, S.; Attwell, S.; Gray, V.; Delcommenne, M.; Troussard, A.; Sanghera, J.; Dedhar, S. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc. Natl. Acad. Sci. USA 2000, 97, 3207-3212.
95. Younes, M.N.; Kim, S.; Yigitbasi, O.G.; Yazici, Y.D.; Jasser, S.A.; Bucana, C.D.; El-Naggar, A.K.; Mills, G.B.; Myers, J.N. Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. Mol. Cancer Ther. 2005, 4, 1146-1156.
96. Bain, J.; Plater, L.; Elliott, M.; Shpiro, N.; Hastie, C.J.; McLauchlan, H.; Klevernic, I.; Arthur, J.S.; Alessi, D.R.; Cohen, P. The selectivity of protein kinase inhibitors: A further update. Biochem. J. 2007, 408, 297-315.
97. Wooldridge, A.A.; MacDonald, J.A.; Erdodi, F.; Ma, C.; Borman, M.A.; Hartshorne, D.J.; Haystead, T.A. Smooth muscle phosphatase is regulated in vivo by exclusion of phosphorylation of threonine 696 of MYPT1 by phosphorylation of Serine 695 in response to cyclic nucleotides. J. Biol. Chem. 2004, 279, 34496-34504.
98. Nakamura, K.; Koga, Y.; Sakai, H.; Homma, K.; Ikebe, M. cGMP-dependent relaxation of smooth muscle is coupled with the change in the phosphorylation of myosin phosphatase. Circ. Res. 2007, 101, 712-722.