283956 Molecular Mechanisms in Durotaxis

Monday, October 29, 2012: 12:48 PM
Somerset East (Westin )
Dennis E. Discher, Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA

On rigid substrates, the cytoskeleton is polarized during cell migration, but extracellular matrix is normally soft.  Here we show that Myosin-IIB (MIIB) is unpolarized in cells on 2D and 3D soft matrix with rear/front polarization emerging as cells migrate onto stiff matrix, including gradients in elasticity relevant to wound-healing. Within Mesenchymal Stem Cells (MSCs) that are known to traffic to stiff scars, MIIB is random on soft matrix but becomes polarized as cells migrate from soft to stiff matrix. This ‘durotaxis’ is more sensitive to MIIB levels than the more abundant, unpolarized Myosin-IIA (MIIA), but Mass Spectrometry suggested that stiffness-dependent changes in phosphorylation of MIIA might play a key role.  Indeed, phospho-Ser1943 in MIIA proves higher on soft matrix versus stiff matrix;  in addition, phosphomimetic-MIIA proves highly mobile in cells, suppresses both MIIA-filamentation and MIIB-polarization on stiff matrix, and ultimately inhibits durotaxis.  Such perturbations and more show that both durotaxis and polarization are maximal at wild-type levels of MIIB expression as coupled to phospho-dynamics of MIIA.  Cytoskeletal polarization thus acts as a highly regulated, mechanosensitive compass in directed migration.  

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