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Vol. 20, Issue 13, 3033-3043, July 1, 2009

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Integrin-linked Kinase Interactions with ELMO2 Modulate Cell Polarity

Ernest Ho^*, Tames Irvine^*, Gregory J.A. Vilk, Gilles Lajoie, Kodi S. Ravichandran, Sudhir J.A. D'Souza^*, and Lina Dagnino^*,

Departments of *Physiology and Pharmacology, and Biochemistry, and Department of Paediatrics, Child Health Research Institute and Lawson Health Research Institute, University of Western Ontario, London, ON, Canada N6A 5C1; and Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22903

Submitted January 16, 2009; Revised April 28, 2009; Accepted May 5, 2009
Monitoring Editor: Asma Nusrat

Cell polarization is a key prerequisite for directed migration during development, tissue regeneration, and metastasis. Integrin-linked kinase (ILK) is a scaffold protein essential for cell polarization, but very little is known about the precise mechanisms whereby ILK modulates polarization in normal epithelia. Elucidating these mechanisms is essential to understand tissue morphogenesis, transformation, and repair. Here we identify a novel ILK protein complex that includes Engulfment and Cell Motility 2 (ELMO2). We also demonstrate the presence of RhoG in ILK–ELMO2 complexes, and the localization of this multiprotein species specifically to the leading lamellipodia of polarized cells. Significantly, the ability of RhoG to bind ELMO is crucial for ILK induction of cell polarization, and the joint expression of ILK and ELMO2 synergistically promotes the induction of front-rear polarity and haptotactic migration. This places RhoG–ELMO2–ILK complexes in a key position for the development of cell polarity and forward movement. Although ILK is a component of many diverse multiprotein species that may contribute to cell polarization, expression of dominant-negative ELMO2 mutants is sufficient to abolish the ability of ILK to promote cell polarization. Thus, its interaction with ELMO2 and RhoG is essential for the ability of ILK to induce front-rear cell polarity.

Address correspondence to: Lina Dagnino (ldagnino{at}uwo.ca)

Abbreviations used: BSA, bovine serum albumin; EMEM, Eagle's minimum essential medium; FBS, fetal bovine serum; ELMO, Engulfment and Cell Motility; GFP, green fluorescent protein; GST, glutathione-S-transferase; ILK, integrin-linked kinase; PEI, polyethyleneimine; TRX, thioredoxin.