TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion.
Bottom Line: Recent studies implicate a role for cell mechanics in cancer progression.Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response.Here we demonstrate that transforming growth factor β (TGF-β)-induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins.
Affiliation: Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.Show MeSH
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Mentions: TGF-β can regulate activation of the RhoA pathway via canonical (activin receptor–like kinase 5 [ALK5] dependent) and noncanonical (mitogen-activated protein kinase dependent) TGF-β signaling mechanisms (Bhowmick et al., 2001). To investigate how TGF-β regulates LARG and GEF-H1 expression during EMT, we used the ALK5 inhibitor SB-431542 (Alk et al., 2002) and found that ALK5 inhibition partially rescued TGF-β–mediated LARG and GEF-H1 protein down-regulation in both NMuMG and OVCA420 cells, indicating a requirement for ALK5 in maximal regulation of RhoGEF expression (Figure 6A). In contrast, blocking the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase pathway with U0126 (Alk et al., 2002), which can also mediate TGF-β responses (Xu et al., 2009), did not ameliorate TGF-β–dependent decreases in LARG and GEF-H1 levels in NMuMG cells (Figure 6A).
Affiliation: Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.