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.
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: Fengming Liu; Liwei Jia; Ann-Marie Thompson-Baine; Jason M Puglise; Martin B A Ter Beest; Mirjam M P Zegers Journal: Mol Cell Biol Date: 2010-02-12 Impact factor: 4.272
Authors: Pei-Yin Ho; Hui Li; Tengis S Pavlov; Roland D Tuerk; Diego Tabares; René Brunisholz; Dietbert Neumann; Alexander Staruschenko; Kenneth R Hallows Journal: J Biol Chem Date: 2018-06-01 Impact factor: 5.157
Authors: Maria Radu; Karen Lyle; Klaus P Hoeflich; Olga Villamar-Cruz; Hartmut Koeppen; Jonathan Chernoff Journal: Mol Cell Biol Date: 2015-09-21 Impact factor: 4.272
Authors: Yinghui Zhang; Lynn Wester; Jichao He; Tamar Geiger; Marja Moerkens; Ram Siddappa; Jean A Helmijr; Mieke M Timmermans; Maxime P Look; Caroline H M van Deurzen; John W M Martens; Chantal Pont; Marjo de Graauw; Erik H J Danen; Els M J J Berns; John H N Meerman; Maurice P H M Jansen; Bob van de Water Journal: Oncogene Date: 2018-01-22 Impact factor: 9.867
Authors: Helen B Pearson; Edwina McGlinn; Toby J Phesse; Holger Schlüter; Anuratha Srikumar; Nathan J Gödde; Christina B Woelwer; Andrew Ryan; Wayne A Phillips; Matthias Ernst; Pritinder Kaur; Patrick Humbert Journal: Mol Cancer Date: 2015-09-17 Impact factor: 27.401
Authors: Nathan J Godde; Julie M Sheridan; Lorey K Smith; Helen B Pearson; Kara L Britt; Ryan C Galea; Laura L Yates; Jane E Visvader; Patrick O Humbert Journal: PLoS Genet Date: 2014-05-22 Impact factor: 5.917
Authors: S R Frank; C P Köllmann; J F van Lidth de Jeude; J R Thiagarajah; L H Engelholm; M Frödin; S H Hansen Journal: Oncogene Date: 2016-09-26 Impact factor: 9.867
Authors: Scott R Frank; Clemens P Köllmann; Phi Luong; Giorgio G Galli; Lihua Zou; André Bernards; Gad Getz; Raffaele A Calogero; Morten Frödin; Steen H Hansen Journal: J Cell Biol Date: 2018-06-22 Impact factor: 10.539