Schematic representation of our findings: A molecular connection between neurofibromin and the Rho/ROCK/LIMK2/cofilin pathway.

A. Upon Rho activation via binding to its RBD (Rho Binding domain), ROCK activates LIMK2 by phosphorylation at its Thr505. Activated LIMK2 will then phosphorylate cofilin on its Ser3, resulting in its inhibition. An invasive phenotype is then observed with accumulation of actin stress fibers. B. SecPH, a new inhibitor of this Rho/ROCK/LIMK2/cofilin pathway. By interacting with LIMK2, SecPH prevents ROCK activation of LIMK2. Our data raises two possible hypotheses for this inhibition of ROCK activation of LIMK2 by SecPH: (1) by steric hindrance, SecPH hides Thr505 of LIMK2 from ROCK accessibility, (2) the PH domain of SecPH substitutes to the PH domain of ROCK by inhibiting the kinase activity of ROCK; this inhibition would specifically occur when ROCK and SecPH are simultaneously bound to LIMK2.



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