title: An ELMO2-RhoG-ILK network modulates microtubule dynamics.
abstract: ELMO2 belongs to a family of scaffold proteins involved in phagocytosis and cell motility. ELMO2 can simultaneously bind integrin-linked kinase (ILK) and RhoG, forming tripartite ERI complexes. These complexes are involved in promoting β1 integrin-dependent directional migration in undifferentiated epidermal keratinocytes. ELMO2 and ILK have also separately been implicated in microtubule regulation at integrin-containing focal adhesions. During differentiation, epidermal keratinocytes cease to express integrins, but ERI complexes persist. Here we show an integrin-independent role of ERI complexes in modulation of microtubule dynamics in differentiated keratinocytes. Depletion of ERI complexes by inactivating the Ilk gene in these cells reduces microtubule growth and increases the frequency of catastrophe. Reciprocally, exogenous expression of ELMO2 or RhoG stabilizes microtubules, but only if ILK is also present. Mechanistically, activation of Rac1 downstream from ERI complexes mediates their effects on microtubule stability. In this pathway, Rac1 serves as a hub to modulate microtubule dynamics through two different routes: 1) phosphorylation and inactivation of the microtubule-destabilizing protein stathmin and 2) phosphorylation and inactivation of GSK-3β, which leads to the activation of CRMP2, promoting microtubule growth. At the cellular level, the absence of ERI species impairs Ca(2+)-mediated formation of adherens junctions, critical to maintaining mechanical integrity in the epidermis. Our findings support a key role for ERI species in integrin-independent stabilization of the microtubule network in differentiated keratinocytes.
authors.affiliation: Department of Physiology and Pharmacology, Children's Health Research Institute, and Lawson Health Research Institute, University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Jackson
authors.affiliation: Department of Physiology and Pharmacology, Children's Health Research Institute, and Lawson Health Research Institute, University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Iordanka A
authors.initials: IA
authors.lastname: Ivanova
authors.affiliation: Department of Physiology and Pharmacology, Children's Health Research Institute, and Lawson Health Research Institute, University of Western Ontario, London, ON N6A 5C1, Canada ldagnino@uwo.ca.
authors.forename: Lina
authors.initials: L
authors.lastname: Dagnino
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008870:Microtubules / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D050777:Stathmin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins; D000099200:Scaffold Protein ILK
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D020558:GTP Phosphohydrolases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D017346:Protein Serine-Threonine Kinases; D050777:Stathmin; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D000099200:Scaffold Protein ILK; C544335:Elmo2 protein, mouse; C484602:Rac1 protein, mouse; C489577:Rhog protein, mouse; C095114:collapsin response mediator protein-2; C000605507:Gsk3b protein, mouse