Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes

Cancer Cell. 2004 Jun;5(6):575-85. doi: 10.1016/j.ccr.2004.05.022.

Abstract

We identified dynein light chain 1 (DLC1) as a physiologic substrate of p21-activated kinase 1 (Pak1). Pak1-DLC1 interaction plays an essential role in cell survival, which depends on Pak1's phosphorylation of DLC1 on Ser88. Pak1 associates with the complex of DLC1 and BimL, a proapoptotic BH3-only protein, and phosphorylates both proteins. Phosphorylation of BimL by Pak1 prevents it from interacting with and inactivation of Bcl-2, an antiapoptotic protein. Overexpression of DLC1 but not DLC1-Ser88Ala mutant promotes cancerous properties of breast cancer cells. DLC1 protein level is elevated in more than 90% of human breast tumors. The regulation of cell survival functions by Pak1-DLC1 interaction represents a novel mechanism by which a signaling kinase might regulate the cancerous phenotypes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine / chemistry
  • Apoptosis*
  • Blotting, Western
  • Breast Neoplasms / pathology
  • Carrier Proteins / pharmacology*
  • Cell Cycle
  • Cell Division
  • Cell Line, Tumor
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Drosophila Proteins*
  • Dyneins
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Glutathione Transferase / metabolism
  • Humans
  • Immunohistochemistry
  • Microscopy, Fluorescence
  • Mutation
  • Neoplasms / pathology*
  • Phenotype
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism*
  • Serine / chemistry
  • Signal Transduction
  • Time Factors
  • Two-Hybrid System Techniques
  • Up-Regulation
  • p21-Activated Kinases

Substances

  • Carrier Proteins
  • Drosophila Proteins
  • Serine
  • Glutathione Transferase
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • Dyneins
  • Alanine