title: The signaling adaptor GAB1 regulates cell polarity by acting as a PAR protein scaffold.
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.
authors.affiliation: Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. zyang@uhnresearch.ca
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Masataka
authors.initials: M
authors.lastname: Umitsu
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ikura
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Muthuswamy
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016764:Cell Polarity / Q000235:genetics*; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C490897:Gab1 protein, mouse; C490894:Gab2 protein, mouse; D008565:Membrane Proteins; C509689:PARD3 protein, human; C499657:PARD6A protein, human; D010750:Phosphoproteins; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases