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 re-entry, 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, non-canonical IGF-1R-Gβγ–phospho(T94)Tctex-1 signaling pathway promotes the proliferation of neural progenitors through modulation of ciliary resorption and G1 length.

PDGFRβ and oncogenic, mutant PDGFRα D842V promote disassembly of primary cilia by a PLCγ and AURKA dependent mechanism

“…1A) or in RPE1 cells that had been treated with serum (Fig. 1B), probably because additional growth factors, such as IGF-1, mediate deciliation in RPE1 cells (Yeh et al, 2013). Accordingly, modest deciliation was observed in RPE1 cells that were treated with IGF-1 or EGF (Fig.…”

“…Serum-induced deciliation has been suggested to involve PDGF signaling (Pugacheva et al, 2007;Tucker et al, 1979), and one study indicates that PDGF-AA, which specifically activates homodimeric PDGFRα (Andrae et al, 2008), induces partial deciliation in RPE1 cells (Yeh et al, 2013), presumably because additional growth factors like IGF-1 are also required (Bielas et al, 2009;Yeh et al, 2013). The mechanism by which PDGF promotes deciliation is unclear, although PI3K has been implicated in the deciliation in fibroblasts that can be induced by a combination of PDGF-AA and IGF-1 (Bielas et al, 2009).…”

Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad

“…1). In mammalian systems, AGS3 is implicated in asymmetric cell division, neuronal plasticity and addiction, autophagy, membrane protein trafficking, polycystic kidney disease, renal response to ischemia, immune cell chemotaxis, insulin-like growth factor-1 mediated ciliary resorption, cardiovascular regulation, and metabolism (Blumer et al, 2002(Blumer et al, , 2006(Blumer et al, , 2008Ghosh et al, 2003;Gotta et al, 2003;Pattingre et al, 2003;Bowers et al, 2004Bowers et al, , 2008Sato et al, 2004;Yao et al, 2005Yao et al, , 2006Groves et al, 2007;Willard et al, 2008;Groves et al, 2010;Nadella et al, 2010;Vural et al, 2010;Hofler and Koelle, 2011;Regner et al, 2011;Chauhan et al, 2012;Kwon et al, 2012;Conley and Watts, 2013;Kamakura et al, 2013;Yeh et al, 2013). AGS3 single nucleotide polymorphisms are associated with diabetes and glucose handling (Scott et al, 2012;Hara et al, 2014;Huyghe et al, 2013).…”

INPP5E interacts with AURKA, linking phosphoinositide signalling to primary cilium stability

“…NRKs induce the resorption of specific sets of cilia on the surface of the organism. Cilia resorption and accelerated G1-S progression has also been shown to be regulated in mammalian cells as a result of insulin-like growth factor 1 (IGF-1)-mediated activation of its receptor, by way of non-canonical Gbc signaling and T94-phosphorylated Tctex-1 present at the base of the cilium (Yeh et al, 2013). Despite these findings, the mechanistic basis for cilium disassembly and, importantly, the inter-relationships between the cell signaling pathways involved, remain to be characterised.…”