title: Structure-function analysis of core STRIPAK Proteins: a signaling complex implicated in Golgi polarization.
abstract: Cerebral cavernous malformations (CCMs) are alterations in brain capillary architecture that can result in neurological deficits, seizures, or stroke. We recently demonstrated that CCM3, a protein mutated in familial CCMs, resides predominantly within the STRIPAK complex (striatin interacting phosphatase and kinase). Along with CCM3, STRIPAK contains the Ser/Thr phosphatase PP2A. The PP2A holoenzyme consists of a core catalytic subunit along with variable scaffolding and regulatory subunits. Within STRIPAK, striatin family members act as PP2A regulatory subunits. STRIPAK also contains all three members of a subfamily of Sterile 20 kinases called the GCKIII proteins (MST4, STK24, and STK25). Here, we report that striatins and CCM3 bridge the phosphatase and kinase components of STRIPAK and map the interacting regions on each protein. We show that striatins and CCM3 regulate the Golgi localization of MST4 in an opposite manner. Consistent with a previously described function for MST4 and CCM3 in Golgi positioning, depletion of CCM3 or striatins affects Golgi polarization, also in an opposite manner. We propose that STRIPAK regulates the balance between MST4 localization at the Golgi and in the cytosol to control Golgi positioning.
authors.affiliation: Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Kean
authors.forename: Derek F
authors.initials: DF
authors.lastname: Ceccarelli
authors.forename: Marilyn
authors.initials: M
authors.lastname: Goudreault
authors.forename: Mario
authors.initials: M
authors.lastname: Sanches
authors.forename: Stephen
authors.initials: S
authors.lastname: Tate
authors.forename: Brett
authors.initials: B
authors.lastname: Larsen
authors.forename: Lucien C D
authors.initials: LC
authors.lastname: Gibson
authors.forename: W Brent
authors.initials: WB
authors.lastname: Derry
authors.forename: Ian C
authors.initials: IC
authors.lastname: Scott
authors.forename: Laurence
authors.initials: L
authors.lastname: Pelletier
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Frank
authors.initials: F
authors.lastname: Sicheri
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000081410:Germinal Center Kinases; D006056:Golgi Apparatus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D051017:Apoptosis Regulatory Proteins; D002148:Calmodulin-Binding Proteins; D000081410:Germinal Center Kinases; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins; C491925:STRN protein, human; C491924:Strn protein, mouse; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2