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.

Coronin 1A depletion restores the nuclear stability and viability of Aip1/Wdr1-deficient neutrophils

“…Second, coronin 1B has been shown to interact with and activate Slingshot phosphatase, thus promoting cofilin dephosphorylation (Cai et al, 2007). That property may be shared by coronin 1A, for its depletion in COS cells has been observed to increase levels of p-cofilin, and interestingly, also of pMLC and cell contractility (Ojeda et al, 2014). Still, given the delicate, fine tuning of the actin dynamics pathways involved in leukocyte cell migration, it is striking to witness that not only did coronin 1A depletion rescue neutrophils from death, but also their full amoeboid motility was restored.…”

Characterization of Novel Molecular Mechanisms Favoring Rac1 Membrane Translocation

“…These clones encoded the β-propeller domain-containing proteins known as Coro1A [35] and WD (tryptophan-aspartic dipeptide) repeat domain 26 (WDR26) as well as two membrane-localized proteins, basigin (Bsg) and transmembrane protein 8A (TMEM8A) ( Fig 1A ). Coro1A is a cytoskeletal regulator [41] that, upon characterization after the foregoing genome-wide functional screen, was demonstrated to be actively involved in both the translocation and downstream effector properties of Rac1 [35, 37, 38]. WDR26 has been linked to the inhibition of both Wnt and Erk pathways, stimulation of phospholipase C-β 2 and the phosphatidylinositol-3 kinase-Akt axis, signaling-connected ubiquitinylation processes, protection against oxidative stress, G β/γ subunit triggered chemotaxis, and cell migration [40, 42–51].…”

“…Interestingly, we have recently described that Coro1A is involved in a myosin II-dependent step downstream of Rac1. This role is signaling branch-specific, since it only affects the responses associated with the engagement of the Rac1-Pak-ArhGEF7 pathway [38]. Due to this downstream function, the elimination of endogenous Coro1A leads to the sequestration of active Rac1-ArhGEF7-Pak complexes in actomyosin ring structures and the generation of large, lamella-like cell protrusions rather than membrane ruffles by cells [38].…”

“…This role is signaling branch-specific, since it only affects the responses associated with the engagement of the Rac1-Pak-ArhGEF7 pathway [38]. Due to this downstream function, the elimination of endogenous Coro1A leads to the sequestration of active Rac1-ArhGEF7-Pak complexes in actomyosin ring structures and the generation of large, lamella-like cell protrusions rather than membrane ruffles by cells [38]. In this effector phase, Coro1A is also involved in the 3D organization of the F-actin cytoskeleton by promoting the bundling and stapling of actin filaments as well as the inhibition of the Arp2/3 complex [67–69].…”

“…This process also requires the interaction of Coro1A with F-actin and ArhGEF7 (also known as β-Pix or Cool1) [35], a GEF that can physically interact with Rac1, Pak, focal adhesion- and cell-cell junction-localized proteins [36]. Further work revealed that this protein also helps coordinating downstream signaling diversification events by active Rac1 in cells [37, 38]. As a result of the foregoing screening, we isolated three additional hits that were also presumably involved in the Rac1 translocation step.…”