A βPIX-PAK2 complex confers protection against Scrib-dependent and cadherin-mediated apoptosis

TY - JOUR

T1 - A βPIX-PAK2 complex confers protection against Scrib-dependent and cadherin-mediated apoptosis

AU - Frank, Scott R

AU - Bell, Jennifer H

AU - Frödin, Morten

AU - Hansen, Steen H

N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.

PY - 2012/10/9

Y1 - 2012/10/9

N2 - 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.

AB - 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.

KW - Adherens Junctions

KW - Animals

KW - Anoikis

KW - Apoptosis

KW - Cadherins

KW - Cell Survival

KW - Dogs

KW - Epithelial Cells

KW - Gene Knockdown Techniques

KW - Guanine Nucleotide Exchange Factors

KW - Intracellular Signaling Peptides and Proteins

KW - Madin Darby Canine Kidney Cells

KW - Osmotic Pressure

KW - Signal Transduction

KW - p21-Activated Kinases

U2 - 10.1016/j.cub.2012.07.011

DO - 10.1016/j.cub.2012.07.011

M3 - Journal article

C2 - 22863318

SN - 0960-9822

VL - 22

SP - 1747

EP - 1754

JO - Current Biology

JF - Current Biology

IS - 19

ER -