Ciliogenesis associated kinase 1: targets and functions in various organ systems

Abstract

Ciliogenesis associated kinase 1 (CILK1) was previously known as intestinal cell kinase because it was cloned from that origin. However, CILK1 is now recognized as a widely expressed and highly conserved serine/threonine protein kinase. Mutations in the human CILK1 gene have been associated with ciliopathies, a group of human genetic disorders with defects in the primary cilium. In mice, both Cilk1 knock-out and Cilk1 knock-in mutations have recapitulated human ciliopathies. Thus, CILK1 has a fundamental role in the function of the cilium. Several candidate substrates have been proposed for CILK1 and the challenge is to relate these to the mutant phenotypes. In this review, we summarize what is known about CILK1 functions and targets, and discuss gaps in current knowledge that motivate further experimentation to fully understand the role of CILK1 in organ development in humans.

Keywords: autophagy; ciliogenesis; ciliopathy; epilepsy; hedgehog signalling; intraflagellar transport; kinesin family member 3A; primary cilia; stereocilia.

Figure 1:

Human CILK1 protein domain structure and the pathogenic variants identified in human ciliopathies and epilepsy. Human CILK1 has two basic structural domains: the N-terminal catalytic domain (4–284 aa) and the C-terminal non-catalytic domain (285–632 aa), which is an intrinsically disordered protein region with critical functions. Three pathogenic mutations (E80K, G120C, and R272Q) in the catalytic domain are associated with ciliopathies. Six pathogenic or likely pathogenic variants located in both the catalytic (I102L and K220E) and the non-catalytic (K305T, V320I, A615T, and R632) domains are associated with epilepsy.

Figure 2:

A working model for CILK1 signalling. The activity of CILK1 can be regulated by phosphorylation of the TDY motif and the conserved N-terminal regulatory site Tyr15. CILK1 is localized to the primary cilium, which provides a unique cellular environment with higher concentration of second messengers such as calcium and cyclic AMP, and many signalling outputs such as GPCR, Hedgehog, PDGFRα, TGFβ, and WNT. How CILK1 is up and down regulated in this unique signalling environment is largely unknown. Four candidate substrates (KIF3A, Scythe, Raptor, and GSK3β) for CILK1 have been identified that can potentially mediate CILK1 effect on cilia structure, signalling, and function. (1) KIF3A is in the kinesin II motor complex that mediates anterograde IFT (intraflagellar transport), which is essential for cilia formation and maintenance. (2) Scythe is a co-chaperone protein that has a critical role in autophagy by modulating the acetylation of p53 and ATG7. Autophagy regulates ciliogenesis by controlling the levels of ciliary proteins IFT20 and OFD1 through autophagic degradation. (3) Raptor is a key regulatory protein for mTOR in mTORC1, which can regulate cilia length or ciliogenesis through an unknown mechanism. (4) GSK3β is a positive regulator of ciliogenesis and ciliary Hedgehog signalling pathway. How these substrates mediate CILK1 effects on cilia morphology and function is still poorly defined.