MIM and cortactin antagonism regulates ciliogenesis and hedgehog signaling.
The primary cilium is critical for transducing Sonic hedgehog (Shh) signaling, but the mechanisms of its transient assembly are poorly understood. Previously we showed that the actin regulatory protein Missing-in-Metastasis (MIM) regulates Shh signaling, but the nature of MIM's role was unknown. Here we show that MIM is required at the basal body of mesenchymal cells for cilia maintenance, Shh responsiveness, and de novo hair follicle formation. MIM knockdown results in increased Src kinase activity and subsequent hyperphosphorylation of the actin regulator Cortactin. Importantly, inhibition of Src or depletion of Cortactin compensates for the cilia defect in MIM knockdown cells, whereas overexpression of Src or phospho-mimetic Cortactin is sufficient to inhibit ciliogenesis. Our results suggest that MIM promotes ciliogenesis by antagonizing Src-dependent phosphorylation of Cortactin and describe a mechanism linking regulation of the actin cytoskeleton with ciliogenesis and Shh signaling during tissue regeneration.
Bershteyn
Marina
M
Stanford University, CA 94305, USA.
Atwood
Scott X
SX
Woo
Wei-Meng
WM
Li
Mischa
M
Oro
Anthony E
AE
D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000502:physiology* / Q000648:ultrastructure; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D018859:Hair Follicle / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000166:cytology; D019061:src-Family Kinases / Q000378:metabolism
D000199:Actins; D051356:Cortactin; D053823:Hedgehog Proteins; D008840:Microfilament Proteins; C473219:Mtss1 protein, mouse; D009363:Neoplasm Proteins; C465570:Shh protein, mouse; D019061:src-Family Kinases