RHO binding to FAM65A regulates Golgi reorientation during cell migration

Directional cell migration involves reorientation of the secretory machinery. However, the molecular mechanisms that control this reorientation are not well characterised. Here, we identify a new Rho effector protein, named FAM65A, which binds to active RHOA, RHOB and RHOC. FAM65A links RHO proteins to Golgi-localising cerebral cavernous malformation-3 protein (CCM3; also known as PDCD10) and its interacting proteins mammalian STE20-like protein kinases 3 and 4 (MST3 and MST4; also known as STK24 and STK26, respectively). Binding of active RHO proteins to FAM65A does not affect the kinase activity of MSTs but results in their relocation from the Golgi in a CCM3-dependent manner. This relocation is crucial for reorientation of the Golgi towards the leading edge and subsequent directional cell migration. Our results reveal a previously unidentified pathway downstream of RHO that regulates the polarity of migrating cells through Golgi reorientation in a FAM65A-, CCM3- and MST3- and MST4-dependent manner.