Article

Nonpolarized signaling reveals two distinct modes of 3D cell migration

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.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2012; 197(3):439-55. DOI: 10.1083/jcb.201201124
Source: PubMed

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.

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    • "Interestingly, blebbistatin appears to have a greater effect on the blebbing process in newly-seeded cells rather than cultured cells, suggesting that blebs are fundamental for cell adhesion; in fact, cells suffer a delay in elongation and remain rounded for longer periods of time. Previous studies have reported that substrate adhesiveness affects the formation of blebs [22,23] . Usually migration through blebbing occurs in confined and non-adhesive environ- ments2829303132 . "
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    • "The protrusion thus produced can be used by the cell to pull itself forward, particularly in confined environments [10]. Lamellipodia (polymerization-based) and blebs (contraction-based) can co-exist, or combine to give hybrid modes such as the lobopodia [11]. The close association of the actin cytoskeleton and the cell membrane means that the membrane could affect the cytoskeleton for purely mechanical reasons, unrelated to the role of the membrane in biochemical signaling cascades. "
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