Abstract
ABSTRACTDirectional 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.
Highlights
Establishment of front–back polarity is crucial for directional migration of mesenchymal-like cells (Etienne-Manneville, 2008)
We report that RHO proteins regulate cell polarity and directional migration by triggering Golgi reorientation through FAM65A: RHOA: RHOB: WCL IP (FAM65A)
We demonstrate that FAM65A is an adaptor protein comprising an N-terminal HR1 domain and a C-terminal Armadillo repeat motif (ARM) domain
Summary
Establishment of front–back polarity is crucial for directional migration of mesenchymal-like cells (Etienne-Manneville, 2008). In addition to the asymmetric organisation of the cytoskeleton, which is achieved through recruitment as well as local synthesis of proteins (Mardakheh et al, 2015), polarised cells reorient their secretory traffic towards the direction of migration (Mellor, 2004). Such exocytic cargos, which originate from the Golgi, contain additional membrane, cell-surface receptors and extracellular matrix components that are required for the maintenance of the leading edge (Mellor, 2004).
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