Abstract
BackgroundEndothelial cells provide a barrier between blood and tissues, which is regulated to allow molecules and cells in out of tissues. Patients with cerebral cavernous malformations (CCM) have dilated leaky blood vessels, especially in the central nervous system. A subset of these patients has loss-of-function mutations in CCM3. CCM3 is part of the STRIPAK protein complex that includes the little-characterized proteins FAM40A and FAM40B.ResultsWe show here that FAM40A and FAM40B can interact with CCM3. Knockdown of CCM3, FAM40A or FAM40B in endothelial cells by RNAi causes an increase in stress fibers and a reduction in loop formation in an in vitro angiogenesis assay, which can be reverted by inhibiting the Rho-regulated ROCK kinases. FAM40B depletion also increases endothelial permeability.ConclusionsThese results demonstrate the importance of the FAM40 proteins for endothelial cell physiology, and suggest that they act as part of the CCM3-containing STRIPAK complex.
Highlights
Endothelial cells provide a barrier between blood and tissues, which is regulated to allow molecules and cells in out of tissues
We find that FAM40A and FAM40B can associate with CCM3, and that all three genes have similar effects in regulating stress fibers and angiogenic loop formation via Rho/ROCK-mediated actomyosin contractility
We found that FAM40A and FAM40B co-immunoprecipitated with CCM3 when they were co-expressed in COS7 cells (Fig. 1b)
Summary
Endothelial cells provide a barrier between blood and tissues, which is regulated to allow molecules and cells in out of tissues. CCM3 has been identified as a component of the STRIPAK (striatin-interacting phosphatase and kinase) complex, which was identified through an interaction map around the protein phosphatase 2A (PP2A) catalytic subunit by an affinity purification/mass spectrometry approach [4]. This STRIPAK complex includes striatin proteins, which are PP2A regulatory subunit proteins and act as protein scaffolds [5], Mob, the GCKIII (germinal centre kinase III) kinases (STK24, STK25 and MST4), another germinal centre kinase MINK1 (misshapen like kinase 1) [6], CCM3, and the FAM40 (FAMily with sequence similarity 40) proteins FAM40A/STRIP1 and FAM40B/STRIP2
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