title: IGF-1 activates a cilium-localized noncanonical Gβγ signaling pathway that regulates cell-cycle progression.
abstract: Primary cilia undergo cell-cycle-dependent assembly and disassembly. Emerging data suggest that ciliary resorption is a checkpoint for S phase reentry and that the activation of phospho(T94)Tctex-1 couples these two events. However, the environmental cues and molecular mechanisms that trigger these processes remain unknown. Here, we show that insulin-like growth-1 (IGF-1) accelerates G1-S progression by causing cilia to resorb. The mitogenic signals of IGF-1 are predominantly transduced through IGF-1 receptor (IGF-1R) on the cilia of fibroblasts and epithelial cells. At the base of the cilium, phosphorylated IGF-1R activates an AGS3-regulated Gβγ signaling pathway that subsequently recruits phospho(T94)Tctex-1 to the transition zone. Perturbing any component of this pathway in cortical progenitors induces premature neuronal differentiation at the expense of proliferation. These data suggest that during corticogenesis, a cilium-transduced, noncanonical IGF-1R-Gβγ-phospho(T94)Tctex-1 signaling pathway promotes the proliferation of neural progenitors through modulation of ciliary resorption and G1 length.
authors: Margaret M. Dyson Vision Research Institute, Department of Ophthalmology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors: Celine
authors: C
authors: Yeh
authors: Aiqun
authors: A
authors: Li
authors: Jen-Zen
authors: JZ
authors: Chuang
authors: Masaki
authors: M
authors: Saito
authors: Alfredo
authors: A
authors: Cáceres
authors: Ching-Hwa
authors: CH
authors: Sung
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002923:Cilia / Q000187:drug effects / Q000378:metabolism*; D004398:Dyneins / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D008954:Models, Biological; D019579:Neocortex / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C533376:DYNLT1 protein, human; C533386:Dynlt1b protein, mouse; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D008934:Mitogens; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D004398:Dyneins
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