Primary Cilia as Signaling Hubs in Health and Disease

Abstract

Primary cilia detect extracellular cues and transduce these signals into cells to regulate proliferation, migration, and differentiation. Here, the function of primary cilia as signaling hubs of growth factors and morphogens is in focus. First, the molecular mechanisms regulating the assembly and disassembly of primary cilia are described. Then, the role of primary cilia in mediating growth factor and morphogen signaling to maintain human health and the potential mechanisms by which defects in these pathways contribute to human diseases, such as ciliopathy, obesity, and cancer are described. Furthermore, a novel signaling pathway by which certain growth factors stimulate cell proliferation through suppression of ciliogenesis is also described, suggesting novel therapeutic targets in cancer.

Keywords: cancer; ciliopathy; obesity; receptor tyrosine kinases; ubiquitin‐mediated protein degradation.

Figure 1

Simplified overview of growth factor and morphogen signaling through primary cilia. A) Primary cilia detect extracellular cues, such as secreted growth factors and morphogens, through their receptors and mediate their signaling to regulate a wide range of activity, including differentiation, cell cycle regulation, metabolism, and neurotransmission. B) Signal transduction processes are impaired when primary cilia are dysfunctional, causing various diseases, such as ciliopathy, obesity, cancer, and neurodevelopmental disorders.

Figure 2

Suppression of ciliogenesis in the presence of growth factors. Activation of RTKs by growth factors phosphorylates USP8, which suppresses the degradation of trichoplein and causes phosphorylation and activation of AurA, resulting in the suppression of ciliogenesis. Serum starvation inactivates RTKs and USP8, which causes degradation of trichoplein that is ubiquitinated by CRL3^KCTD17 and destabilization of AurA, resulting in ciliogenesis.

Figure 3

EGF signaling connects mechanosensation to primary cilia. A) When EGF signaling is activated, PtdIns(4,5)P₂ is phosphorylated by PI3K, which decreases and increases the local concentration of PtdIns(4,5)P₂ and PtdIns(3,4,5)P₃, respectively, resulting in the activation of PKD2. B) When EGF signaling is absent, the local concentration of PtdIns(4,5)P₂ and PtdIns(3,4,5)P₃ is increased and decreased, respectively, resulting in the suppression of PKD2. By changing the sensitivity of PKD2, EGF signaling regulates mechanosensation.

Figure 4

TGFβ signaling is involved in left‐right asymmetry regulated by primary cilia. The ventral node of the mammalian embryo or an equivalent structure in other vertebrates consists of pit cells and perinodal (crown) cells. Cerl2, Nodal, and Gdf1 proteins are expressed bilaterally in the crown cells. When the immotile cilia of crown cells sense the leftward flow generated by the rotational movement of motile cilia of pit cells, the Cerl2 mRNA is degraded on the left side crown cells, which causes the formation of Nodal‐Gdf1 heterodimers. The Nodal‐Gdf1 heterodimers travel to the left side of the LPM and bind to TGFβ receptors, resulting in left‐side morphogenesis through the expression of target genes, including Lefty2 and Pitx2.

Figure 5

IGF signaling modulates corticogenesis through primary cilia. A) Radial glial cells located in the ventricular zone protrude primary cilia into lateral ventricles filled with cerebrospinal fluid. B) (i) IGF1 secreted into the cerebrospinal fluid from the choroid plexus binds to IGF1R located on primary cilia of radial glial cells and phosphorylates it. (ii) The phosphorylated IGF1R binds to Gα, which (iii) liberates Gβγ, (iv) triggers the release of Tctex‐1 from the dynein complex, (v) promotes the phosphorylation of Tctex‐1 and recruits the phosphorylated Tctex‐1 to the transition zone. (vi) The phosphorylated Tctex‐1 stimulates the resorption of primary cilia and S phase progression. Shortening G1 increases the proliferation of RG, whereas lengthening G1 stimulates differentiation of radial glial cells into neurons.

Figure 6

Leptin signaling modulates appetite through primary cilia. The arcuate nucleus is composed of different types of ciliated neurons, including anorexigenic neurons expressing POMC and orexigenic neurons expressing AgRP. If leptin binds to its receptor in ciliated neurons, the transcription of POMC and AgRP is increased and decreased, respectively, through the JAK‐STAT3 pathway. αMSH, cleaved from POMC, also acts as the anorexigenic neuropeptide. MC4R, a common receptor for αMSH and AgRP, and ADCY3 are localized in ciliated PVN neurons expressing SIM1. αMSH and AgRP activate and inhibit MC4R, respectively. ADCY3 is bound to Gs in primary cilia. Inhibition of Gs in SIM1‐expressing neurons is sufficient to cause obesity.

Figure 7

Hedgehog signaling relates cancer cell proliferation through primary cilia. In cancer cells with amplification of SHH, SHH binds to PTCH1, which causes the accumulation of SMO in primary cilia, resulting in the conversion of Gli to Gli^A and translocation of Gli^A to nucleus. The transcription of SHH target genes is activated by Gli^A. A) If the primary cilium is lost, the cilium‐dependent conversion of Gli^A is inhibited, resulting in the suppression of proliferation. In cancer cells with amplification of Gli, the amount of Gli^A can increase without the help of SMO (independent of primary cilia). B) In the absence of SHH, primary cilia increase the conversion of Gli to Gli^R, which inhibits the transcription of SHH target genes. Primary cilia can A) promote and B) suppress the tumorigenesis, depending on the context.

Figure 8

Mechanisms underlying the loss of primary cilia frequently observed in cancer cells with aberrant RTK. Activation of RTKs deciliates primary cilia through activation of the USP8‐trichoplein‐AurA pathway. Other USPs, such as USP54 and UCHL3, may be involved in the deciliation induced by activation of RTKs. A) The suppression of ciliogenesis stimulates cell proliferation, which is independent of the stimulation of cell proliferation through the Ras‐Raf and PI3K‐AKT cascades. B) Inhibition of deubiquitinases, such as USP8, suppresses the trichoplein‐AurA pathway, resulting in forced ciliation, which can suppress cell proliferation independently of the Ras‐Raf and PI3K‐AKT cascades.