title: Distinct signaling mechanisms regulate migration in unconfined versus confined spaces.
abstract: Using a microchannel assay, we demonstrate that cells adopt distinct signaling strategies to modulate cell migration in different physical microenvironments. We studied α4β1 integrin-mediated signaling, which regulates cell migration pertinent to embryonic development, leukocyte trafficking, and melanoma invasion. We show that α4β1 integrin promotes cell migration through both unconfined and confined spaces. However, unlike unconfined (2D) migration, which depends on enhanced Rac1 activity achieved by preventing α4/paxillin binding, confined migration requires myosin II-driven contractility, which is increased when Rac1 is inhibited by α4/paxillin binding. This Rac1-myosin II cross talk mechanism also controls migration of fibroblast-like cells lacking α4β1 integrin, in which Rac1 and myosin II modulate unconfined and confined migration, respectively. We further demonstrate the distinct roles of myosin II isoforms, MIIA and MIIB, which are primarily required for confined and unconfined migration, respectively. This work provides a paradigm for the plasticity of cells migrating through different physical microenvironments.
authors: Department of Chemical and Biomolecular Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
authors: Wei-Chien
authors: WC
authors: Hung
authors: Shih-Hsun
authors: SH
authors: Chen
authors: Colin D
authors: CD
authors: Paul
authors: Kimberly M
authors: KM
authors: Stroka
authors: Ying-Chun
authors: YC
authors: Lo
authors: Joy T
authors: JT
authors: Yang
authors: Konstantinos
authors: K
authors: Konstantopoulos
mesh_terms: D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D039441:Integrin alpha4 / Q000737:chemistry / Q000235:genetics; D039041:Integrin alpha4beta1 / Q000378:metabolism; D019169:Jurkat Cells; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D024462:Myosin Type II / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D039041:Integrin alpha4beta1; D050505:Mutant Proteins; D051419:Paxillin; D039441:Integrin alpha4; C472645:blebbistatin; D024462:Myosin Type II; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
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