Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation

Dev Cell. 2008 Feb;14(2):205-15. doi: 10.1016/j.devcel.2007.11.021.

Abstract

A polarity complex of PAR-3, PAR-6, and atypical protein kinase C (aPKC) functions in various cell polarization events. PAR-3 directly interacts with Tiam1/Taim2 (STEF), Rac1-specific guanine nucleotide exchange factors, and forms a complex with aPKC-PAR-6-Cdc42*GTP, leading to Rac1 activation. RhoA antagonizes Rac1 in certain types of cells. However, the relationship between RhoA and the PAR complex remains elusive. We found here that Rho-kinase/ROCK/ROK, the effector of RhoA, phosphorylated PAR-3 at Thr833 and thereby disrupted its interaction with aPKC and PAR-6, but not with Tiam2. Phosphorylated PAR-3 was observed in the leading edge, and in central and rear portions of migrating cells having front-rear polarity. Knockdown of PAR-3 by small interfering RNA (siRNA) impaired cell migration, front-rear polarization, and PAR-3-mediated Rac1 activation, which were recovered with siRNA-resistant PAR-3, but not with the phospho-mimic PAR-3 mutant. We propose that RhoA/Rho-kinase inhibits PAR complex formation through PAR-3 phosphorylation, resulting in Rac1 inactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cell Movement
  • Cell Polarity
  • Chlorocebus aethiops
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Multiprotein Complexes / metabolism*
  • Phosphorylation
  • Phosphothreonine / metabolism
  • Pseudopodia / metabolism
  • Rats
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / metabolism
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Carrier Proteins
  • Multiprotein Complexes
  • Phosphothreonine
  • rho-Associated Kinases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein