Coronin1 Proteins Dictate Rac1 Intracellular Dynamics and Cytoskeletal Output

Abstract

Rac1 regulates lamellipodium formation, myosin II-dependent contractility, and focal adhesions during cell migration. While the spatiotemporal assembly of those processes is well characterized, the signaling mechanisms involved remain obscure. We report here that the cytoskeleton-related Coronin1A and -1B proteins control a myosin II inactivation-dependent step that dictates the intracellular dynamics and cytoskeletal output of active Rac1. This step is signaling-branch specific, since it affects the functional competence of active Rac1 only when forming complexes with downstream ArhGEF7 and Pak proteins in actomyosin-rich structures. The pathway is used by default unless Rac1 is actively rerouted away from the structures by upstream activators and signals from other Rho GTPases. These results indicate that Coronin1 proteins are at the center of a regulatory hub that coordinates Rac1 activation, effector exchange, and the F-actin organization state during cell signaling. Targeting this route could be useful to hamper migration of cancer cells harboring oncogenic RAC1 mutations.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00347-14.

ACKNOWLEDGMENTS

We thank M. Blázquez and personnel of the CIC Microscopy and Genomics and Proteomics Units for technical assistance and M. Vicente-Manzanares and M. Dosil for comments on the manuscript.

X.R.B.'s work has been funded by the Spanish Ministry of Economy and Competitiveness (SAF2009-07172, SAF2012-3171, RD06/0020/0001, and RD12/0036/0002), the Castilla-León Autonomous Government (CSI101U13), and the Asociación Española Contra el Cáncer. V.O.'s position has been supported by a JAE-Predoc contract (CSIC) and grant no. RD12/0036/0002. Spanish funding is cosponsored by the European Regional Development Fund.

V.O. carried out experimental work, analyzed data, edited figures, and wrote initial manuscript drafts. A.C.-C. generated reagents used in the work. X.R.B. directed the work, analyzed data, and wrote the manuscript.

We declare that we have no conflicts of interest.