A βPIX-PAK2 Complex Confers Protection against Scrib-Dependent and Cadherin-Mediated Apoptosis

Background: During epithelial morphogenesis, a complex comprising the beta PIX (PAK-interacting exchange factor beta) 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 beta PIX 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-beta PIX-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 beta PIX and PAK2 to adherens junctions where a beta PIX-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-beta PIX-PAK2 complex functions to regulate anoikis elicited by cadherin engagement, with Scrib promoting and the beta PIX-PAK2 complex suppressing anoikis, respectively. Conclusions: Our findings demonstrate that the Scrib-beta PIX-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-beta PIX-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.