ZIP kinase, a key regulator of myosin protein phosphatase 1.
Two major physiological roles have been defined for zipper interacting protein kinase (ZIPK), regulation of apoptosis in non-muscle cells and regulation of Ca(2+) sensitization in smooth muscle. Although much attention has focused on the role of ZIPK in the regulation of apoptotic events, its roles in smooth muscle are likely to have equal if not greater physiological relevance. We first identified ZIPK as a major protein kinase controlling the phosphorylation of myosin phosphatase (SMPP-1M) and the inhibitor protein CPI17 in smooth muscle. Phosphorylation of SMPP-1M and CPI17 by ZIPK inhibits phosphatase activity towards myosin and causes profound Ca(2+) sensitization and contraction in smooth muscle. ZIPK will also directly phosphorylate both muscle and non-muscle myosin. The highly selective actions of ZIPK in the control of myosin phosphorylation potentially make the enzyme an ideal candidate for the development of novel therapeutics to treat smooth muscle related disorders such as hypertension or asthma.
Haystead
Timothy A J
TA
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. hayst001@mc.duke.edu
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D064550:Death-Associated Protein Kinases; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism*; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D064550:Death-Associated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054645:Protein Phosphatase 1; D043263:Myosin-Light-Chain Phosphatase; D009218:Myosins; D002118:Calcium