title: Nonpolarized signaling reveals two distinct modes of 3D cell migration.
abstract: We search in this paper for context-specific modes of three-dimensional (3D) cell migration using imaging for phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and active Rac1 and Cdc42 in primary fibroblasts migrating within different 3D environments. In 3D collagen, PIP3 and active Rac1 and Cdc42 were targeted to the leading edge, consistent with lamellipodia-based migration. In contrast, elongated cells migrating inside dermal explants and the cell-derived matrix (CDM) formed blunt, cylindrical protrusions, termed lobopodia, and Rac1, Cdc42, and PIP3 signaling was nonpolarized. Reducing RhoA, Rho-associated protein kinase (ROCK), or myosin II activity switched the cells to lamellipodia-based 3D migration. These modes of 3D migration were regulated by matrix physical properties. Specifically, experimentally modifying the elasticity of the CDM or collagen gels established that nonlinear elasticity supported lamellipodia-based migration, whereas linear elasticity switched cells to lobopodia-based migration. Thus, the relative polarization of intracellular signaling identifies two distinct modes of 3D cell migration governed intrinsically by RhoA, ROCK, and myosin II and extrinsically by the elastic behavior of the 3D extracellular matrix.
authors.affiliation: Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA. petrier@mail.nih.gov
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Petrie
authors.forename: Núria
authors.initials: N
authors.lastname: Gavara
authors.forename: Richard S
authors.initials: RS
authors.lastname: Chadwick
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Yamada
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002450:Cell Communication; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D018625:Microscopy, Atomic Force; D024462:Myosin Type II / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011554:Pseudopodia / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; D034741:RNA, Small Interfering; C060974:phosphatidylinositol 3,4,5-triphosphate; D054460:rho-Associated Kinases; D024462:Myosin Type II; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein