Protein kinase A governs a RhoA–RhoGDI protrusion–retraction pacemaker in migrating cells

Abstract

The cyclical protrusion and retraction of the leading edge is a hallmark of many migrating cells involved in processes such as development, inflammation and tumorigenesis. The molecular identity of the signalling mechanisms that control these cycles has remained unknown. Here, we used live-cell imaging of biosensors to monitor spontaneous morphodynamic and signalling activities, and employed correlative image analysis to examine the role of cyclic-AMP-activated protein kinase A (PKA) in protrusion regulation. PKA activity at the leading edge is closely synchronized with rapid protrusion and with the activity of RhoA. Ensuing PKA phosphorylation of RhoA and the resulting increased interaction between RhoA and RhoGDI (Rho GDP-dissociation inhibitor) establish a negative feedback mechanism that controls the cycling of RhoA activity at the leading edge. Thus, cooperation between PKA, RhoA and RhoGDI forms a pacemaker that governs the morphodynamic behaviour of migrating cells. Live-cell imaging of the spatiotemporal kinetics of PKA activation during cell migration reveals that PKA regulates the protrusion and retraction cycle of the leading edge. Protrusion formation correlates with RhoA and PKA activation. PKA subsequently phosphorylates RhoA to increase its interaction with RhoGDI and terminate RhoA activity at the leading edge.

Cite this article

Tkachenko, E., Sabouri-Ghomi, M., Pertz, O. et al. Protein kinase A governs a RhoA–RhoGDI protrusion–retraction pacemaker in migrating cells. Nat Cell Biol 13, 660–667 (2011). https://doi.org/10.1038/ncb2231

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