Goh LL, Manser E

Rnd proteins are Rho family GTP binding proteins with cellular functions that antagonize RhoA signaling. We recently described a new Rnd3 effector Syx, also named PLEKHG5 that interacts with Rnds via a Raf1-like 'Ras binding domain'. Syx is a multi-domain RhoGEF that participates in early zebrafish development. Here we demonstrated ...

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that Rnd1, Rnd2 and Rnd3 stability is acutely dependent on interaction with their effectors such as Syx or p190RhoGAP. Although Rnd3 turnover is blocked by treatment of cells with MG132, we provide evidence that such turnover is mediated indirectly by effects on the Rnd3 effectors, rather than on Rnd3 itself, which is not significantly ubiquitinated. The minimal regions of Syx and p190RhoGAP that bind Rnd3 are not sequence related but have similar effects. We have identified features that allow for Rnd3 turnover including a conserved Lys-45 close to the switch I region and the C-terminal membrane-binding domain of Rnd3, which cannot be substituted by the equivalent Cdc42 CAAX sequence. By contrast an effector binding defective mutant of Rnd3 when over-expressed undergoes turnover at normal rates. Interestingly the activity of the RhoA regulated kinase ROCK stimulates Rnd3 turnover. This study suggests Rnd proteins are regulated through feedback mechanisms in cells where the level of effectors and RhoA activity influence the stability of Rnd proteins. This effector feedback behaviour is analogous to the ability of ACK1 and PAK1 to prolong the life-time of the active GTP-bound state of Cdc42 and Rac1.

Date: Jul. 17, 2012

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