Abstract
Cell migration is essential to embryonic development, wound healing, and cancer cell dissemination. Cells move via leading-edge protrusion, substrate adhesion, and retraction of the cell's rear. The molecular mechanisms by which extracellular cues signal to the actomyosin cytoskeleton to control these motility mechanics are poorly understood. The growth factor-responsive and oncogenically activated protein extracellular signal-regulated kinase (ERK) promotes motility by signaling in actin polymerization-mediated edge protrusion. Using a combination of immunoblotting, co-immunoprecipitation, and myosin-binding experiments and cell migration assays, we show here that ERK also signals to the contractile machinery through its substrate, p90 ribosomal S6 kinase (RSK). We probed the signaling and migration dynamics of multiple mammalian cell lines and found that RSK phosphorylates myosin phosphatase–targeting subunit 1 (MYPT1) at Ser-507, which promotes an interaction of Rho kinase (ROCK) with MYPT1 and inhibits myosin targeting. We find that by inhibiting the myosin phosphatase, ERK and RSK promote myosin II–mediated tension for lamella expansion and optimal edge dynamics for cell migration. These findings suggest that ERK activity can coordinately amplify both protrusive and contractile forces for optimal cell motility.
Highlights
Cell migration is essential to embryonic development, wound healing, and cancer cell dissemination
We found that the extracellular signalregulated kinase (ERK)-regulated p90 ribosomal S6 kinase (RSK) phosphorylates myosin phosphatase– targeting subunit 1 (MYPT1) at Ser-507, and this promotes inhibitory phosphorylations on Myosin light chain phosphatase (MLCP), cell motility, and lamella edge dynamics
To identify ERK-mediated myosin II regulatory mechanisms, we searched for phospho-signals to the myosin machinery that might be mediated by RSK
Summary
MLC phosphorylation in the leading edge of migrating cells is dynamic. Phosphorylation and myosin activation occurs at the tip of protruding edges and increases during an initial slow phase of retraction [33]. MYLK and ROCK have partially overlapping functions in these edge dynamics and cell migration. MYLK and MYPT1 inhibition block migration persistence, a measurement of how well cells maintain their direction of motion. An optimal balance of MYLK-phosphorylated and MLCP-dephosphoryated MLC pools enables migration persistence. ERK can directly phosphorylate and activate MYLK in vitro, suggesting a mechanism by which ERK might regulate myosin contractility [15, 25]. We found that the ERK-regulated p90 ribosomal S6 kinase (RSK) phosphorylates MYPT1 at Ser-507, and this promotes inhibitory phosphorylations on MLCP, cell motility, and lamella edge dynamics
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