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The COOH terminus of Rho-kinase negatively regulates rho-kinase activity.

Abstract
Rho-kinase is implicated in the phosphorylation of myosin light chain downstream of Rho, which is thought to induce smooth muscle contraction and stress fiber formation in non-muscle cells. Here, we examined the mode of action of inhibitors of Rho-kinase. The chemical compounds such as HA1077 and Y-32885 inhibited not only the Rho-kinase activity but also the activity of protein kinase N, one of the targets of Rho, but had less of an effect on the activity of myotonic dystrophy kinase-related Cdc42-binding kinase beta (MRCKbeta). The COOH-terminal portion of Rho-kinase containing Rho-binding (RB) and pleckstrin homology (PH) domains (RB/PH (TT)), in which point mutations were introduced to abolish the Rho binding activity, interacted with Rho-kinase and thereby inhibited the Rho-kinase activity, whereas RB/PH (TT) had no effect on the activity of protein kinase N or MRCKbeta, suggesting that the COOH-terminal region of Rho-kinase is a possible negative regulatory region of Rho-kinase. The expression of RB/PH (TT) specifically blocked the stress fiber and focal adhesion formation induced by the active form of Rho or Rho-kinase in NIH 3T3 cells, but not that induced by the active form of MRCKbeta or myosin light chain. Thus, RB/PH (TT) appears to specifically inhibit Rho-kinase in vivo.
AuthorsM Amano, K Chihara, N Nakamura, T Kaneko, Y Matsuura, K Kaibuchi
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 45 Pg. 32418-24 (Nov 05 1999) ISSN: 0021-9258 [Print] United States
PMID10542285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Myosin Light Chains
  • Peptide Fragments
  • Protein Serine-Threonine Kinases
  • rho-Associated Kinases
Topics
  • 3T3 Cells
  • Animals
  • Chromatography, Affinity
  • Cytoskeleton (metabolism)
  • Enzyme Inhibitors (pharmacology)
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Myosin Light Chains (metabolism)
  • Peptide Fragments (metabolism)
  • Phosphorylation
  • Protein Serine-Threonine Kinases (chemistry, metabolism)
  • Structure-Activity Relationship
  • Substrate Specificity
  • rho-Associated Kinases

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