p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus

J Biol Chem. 2003 Dec 26;278(52):52919-23. doi: 10.1074/jbc.M309334200. Epub 2003 Oct 6.

Abstract

p57Kip2 is the only cyclin-dependent kinase (Cdk) inhibitor shown to be essential for mouse embryogenesis. The fact suggests that p57 has a specific role that cannot be compensated by other Cdk inhibitors. LIM-kinase 1 (LIMK-1) is a downstream effector of the Rho family of GTPases that phosphorylates and inactivates an actin depolymerization factor, cofilin, to induce the formation of actin fiber. Here we demonstrate that p57 regulates actin dynamics by binding and translocating LIMK-1 from the cytoplasm into the nucleus, which in turn results in a reorganization of actin fiber. The central region of p57, a unique feature among the Cdk inhibitors, and the N-terminal region of LIMK-1, which contains the LIM domains were essential for the interaction. Expression of p57, but not p27Kip1 or a p57 mutant, with a deletion in the central region was shown to induce marked reorganization of actin filament and a translocation of LIMK-1. Our findings indicate p57 may act as a key regulator in embryogenesis by bearing two distinct functions, the regulation of cell cycle through binding to Cdks and the regulation of actin dynamics through binding to LIMK-1, both of which should be important in developmental procedure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry
  • Actins / metabolism*
  • Active Transport, Cell Nucleus
  • Animals
  • COS Cells
  • Cell Cycle
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Nucleus / metabolism*
  • Cells
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinase Inhibitor p57
  • Cytoplasm / metabolism
  • DNA, Complementary / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Library
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Lim Kinases
  • Mice
  • Models, Biological
  • Mutation
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Osteoblasts / metabolism
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein Kinases / metabolism*
  • Protein Structure, Tertiary
  • Protein Transport
  • Transfection
  • Tumor Suppressor Proteins / metabolism
  • Two-Hybrid System Techniques

Substances

  • Actins
  • CDKN1C protein, human
  • Cdkn1b protein, mouse
  • Cdkn1c protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p57
  • DNA, Complementary
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein Kinases
  • LIMK1 protein, human
  • Lim Kinases
  • Limk1 protein, mouse