title: A βPIX-PAK2 complex confers protection against Scrib-dependent and cadherin-mediated apoptosis.
abstract: BACKGROUND
  During epithelial morphogenesis, a complex comprising the βPIX (PAK-interacting exchange factor β) and class I PAKs (p21-activated kinases) is recruited to adherens junctions. Scrib, the mammalian ortholog of the Drosophila polarity determinant and tumor suppressor Scribble, binds βPIX directly. Scrib is also targeted to adherens junctions by E-cadherin, where Scrib strengthens cadherin-mediated cell-cell adhesion. Although a role for the Scrib-βPIX-PAK signaling complex in promoting membrane protrusion at wound edges has been elucidated, a function for this complex at adherens junctions remains unknown.
  
  
  RESULTS
  Here, we establish that Scrib targets βPIX and PAK2 to adherens junctions where a βPIX-PAK2 complex counterbalances apoptotic stimuli transduced by Scrib and elicited by cadherin-mediated cell-cell adhesion. Moreover, we show that this signaling pathway regulates cell survival in response to osmotic stress. Finally, we determine that in suspension cultures, the Scrib-βPIX-PAK2 complex functions to regulate anoikis elicited by cadherin engagement, with Scrib promoting and the βPIX-PAK2 complex suppressing anoikis, respectively.
  
  
  CONCLUSIONS
  Our findings demonstrate that the Scrib-βPIX-PAK2 signaling complex functions as an essential modulator of cell survival when localized to adherens junctions of polarized epithelia. The activity of this complex at adherens junctions is thereby essential for normal epithelial morphogenesis and tolerance of physiological stress. Furthermore, when localized to adherens junctions, the Scrib-βPIX-PAK2 signaling complex serves as a key determinant of anoikis sensitivity, a pivotal mechanism in tumor suppression. Thus, this work also reveals the need to expand the definition of anoikis to include a central role for adherens junctions.
authors.affiliation: GI Cell Biology Research Laboratory, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Frank
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Bell
authors.forename: Morten
authors.initials: M
authors.lastname: Frödin
authors.forename: Steen H
authors.initials: SH
authors.lastname: Hansen
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D023102:Anoikis; D017209:Apoptosis / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism*; D002470:Cell Survival; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects / Q000378:metabolism; D009997:Osmotic Pressure; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D054462:p21-Activated Kinases