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.
Institute of Cancer Research, Division of Cancer Biology, 237 Fulham Road, London SW3 6JB, UK mardakheh@icr.ac.uk.
Faraz K
0000-0003-3896-0827
FK
Mardakheh
Institute of Cancer Research, Division of Cancer Biology, 237 Fulham Road, London SW3 6JB, UK.
Annette
0000-0001-9436-5147
A
Self
Institute of Cancer Research, Division of Cancer Biology, 237 Fulham Road, London SW3 6JB, UK.
Christopher J
CJ
Marshall
D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002465:Cell Movement; D004789:Enzyme Activation; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000099317:Hippo Kinases
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D020741:rho GTP-Binding Proteins; C495390:PDCD10 protein, human; C000621640:RIPOR1 protein, human; C109163:STK24 protein, human; D000099317:Hippo Kinases; C430908:STK26 protein, human
CCM3; Cerebral cavernous malformation; FAM65A; Golgi orientation; MST4; Rho-GTPases