Figure 2. Cilia-associated signaling pathways relevant to cancer.
A. NEDD9 and AURKA at the basal body initiate ciliary disassembly through the activation of HDAC6 and other substrates. Ca2+-liganded CALM and a PLK1-DVL2 complex support the activation of AURKA, while BUBR1 limits DVL2 expression during ciliogenesis. Altered function of AURKA, NEDD9, PLK1 and BUBR1 contributes to oncogenesis by targeting cell cycle progression and other cellular processes. HDAC6, histone deacetylase 6; PLK1, polo-like kinase 1; DVL2, dishevelled-2; AURKA, aurora-A kinase; NEDD9, neural precursor expressed downregulated in development 9; BUBR1, budding uninhibited by benzimidazoles 1-related protein kinase; CALM, calmodulin. B. Renal fluid flow activates ciliary LKB1, which signals through AMPK and the TSC1/TSC2 heterodimer to limit mTOR signaling and cell growth. Ablation of the cilium stimulates cell growth by relieving mTOR inhibition. LKB1 negatively regulates NEDD9; TSC2 limits PLK1. LKB1, liver kinase B1 (also known as serine/threonine-protein kinase STK11); AMPK, 5′-AMP-activated protein kinase; TSC1, hamartin; TSC2, tuberin; mTOR, mammalian target of rapamycin. C. LKB1 signaling to AMPK is in part mediated through the activity of SREBPs, which regulate ciliary stability and activate FASN. Active FASN modifies and alters activity of the ciliary-responsive protein WNT, influencing activity of cytosolic β-catenin, NEDD9, and other oncogenic proteins. SREBP1, sterol regulatory element-binding protein 1; FASN, fatty acid synthase. D. In the presence of oxygen, VHL degrades HIFα; during hypoxia, HIFα induces transcription of angiogenesis promoting factors including VEGF, PDGF, and EPO, as well as NEDD9 and AURKA. VHL in cooperation with PTEN and GSK3 maintains the cilium by stabilizing and orienting microtubules (MT). Additional functions of VHL include the regulation of cell junctions and ECM composition. The depletion of VHL can drive oncogenesis via these various cell processes. GSK3, glycogen synthase kinase 3; PTEN, phosphatase and tensin homolog; VHL, von Hippel-Lindau; HIFα, hypoxia-inducible factor alpha; VEGF, vascular endothelial growth factor; PDGF, platelet derived growth factor; EPO, erythropoietin.