The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones

Genes Dev. 2005 Oct 1;19(19):2307-19. doi: 10.1101/gad.1340605.

Abstract

LIM kinase 1 (LIMK1) controls important cellular functions such as morphogenesis, cell motility, tumor cell metastasis, development of neuronal projections, and growth cone actin dynamics. We have investigated the role of the RING finger protein Rnf6 during neuronal development and detected high Rnf6 protein levels in developing axonal projections of motor and DRG neurons during mouse embryogenesis as well as cultured hippocampal neurons. RNAi-mediated knock-down experiments in primary hippocampal neurons identified Rnf6 as a regulator of axon outgrowth. Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons. Rnf6 is functionally linked to LIMK1 during the development of axons, as the changes in axon outgrowth induced by up- or down-regulation of Rnf6 levels can be restored by modulation of LIMK1 expression. Thus, these results assign a specific role for Rnf6 in the control of cellular LIMK1 concentrations and indicate a new function for the ubiquitin/proteasome system in regulating local growth cone actin dynamics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • CHO Cells
  • COS Cells
  • Chlorocebus aethiops
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Developmental / physiology*
  • Growth Cones / enzymology*
  • Hippocampus / cytology
  • Hippocampus / embryology*
  • Humans
  • Lim Kinases
  • Mice
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Ubiquitin / metabolism

Substances

  • Actins
  • DNA-Binding Proteins
  • RNA, Small Interfering
  • RNF6 protein, human
  • Ubiquitin
  • Protein Kinases
  • LIMK1 protein, human
  • Lim Kinases
  • Limk1 protein, mouse
  • Proteasome Endopeptidase Complex