The signaling adaptor GAB1 regulates cell polarity by acting as a PAR protein scaffold

Mol Cell. 2012 Aug 10;47(3):469-83. doi: 10.1016/j.molcel.2012.06.037.

Abstract

Cell polarity plays a key role in development and is disrupted in tumors, yet the molecules and mechanisms that regulate polarity remain poorly defined. We found that the scaffolding adaptor GAB1 interacts with two polarity proteins, PAR1 and PAR3. GAB1 binds PAR1 and enhances its kinase activity. GAB1 brings PAR1 and PAR3 into a transient complex, stimulating PAR3 phosphorylation by PAR1. GAB1 and PAR6 bind the PAR3 PDZ1 domain and thereby compete for PAR3 binding. Consequently, GAB1 depletion causes PAR3 hypophosphorylation and increases PAR3/PAR6 complex formation, resulting in accelerated and enhanced tight junction formation, increased transepithelial resistance, and lateral domain shortening. Conversely, GAB1 overexpression, in a PAR1/PAR3-dependent manner, disrupts epithelial apical-basal polarity, promotes multilumen cyst formation, and enhances growth factor-induced epithelial cell scattering. Our results identify GAB1 as a negative regulator of epithelial cell polarity that functions as a scaffold for modulating PAR protein complexes on the lateral membrane.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Caco-2 Cells
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Polarity / genetics*
  • Dogs
  • HEK293 Cells
  • Humans
  • Kidney / cytology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Binding / genetics
  • Protein Structure, Tertiary / genetics
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Gab1 protein, mouse
  • Gab2 protein, mouse
  • Membrane Proteins
  • PARD3 protein, human
  • PARD6A protein, human
  • Phosphoproteins
  • MARK2 protein, human
  • Protein-Serine-Threonine Kinases