Acute Inhibition of Heterotrimeric Kinesin-2 Function Reveals Mechanisms of Intraflagellar Transport in Mammalian Cilia

Engelke, Martin F.; Waas, Bridget; Kearns, Sarah; Suber, Ayana; Boss, Allison; Allen, Benjamin L.; Verhey, Kristen J.

doi:10.1016/j.cub.2019.02.043

Cited by 62 publications

(60 citation statements)

References 67 publications

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“…The molecular mechanisms underlying CAPK signaling and ciliary functions are still largely unknown. In primary cilia, kinesin-2 motor complex (KIF3A/KIF3B/KAP3) mediates anterograde intraflagellar transport (IFT) which is critical for cilium formation and maintenance [19]. KIF3A has been proposed as a direct substrate of CAPK [7].…”

Section: Introductionmentioning

confidence: 99%

Ciliopathy-Associated Protein Kinase ICK Requires Its Non-Catalytic Carboxyl-Terminal Domain for Regulation of Ciliogenesis

Wang

Gailey

et al. 2019

Cells

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Loss-of-function mutations in the human ICK (intestinal cell kinase) gene cause dysfunctional primary cilia and perinatal lethality which are associated with human ciliopathies. The enzyme that we herein call CAPK (ciliopathy-associated protein kinase) is a serine/threonine protein kinase that has a highly conserved MAPK-like N-terminal catalytic domain and an unstructured C-terminal domain (CTD) whose functions are completely unknown. In this study, we demonstrate that truncation of the CTD impairs the ability of CAPK to interact with and phosphorylate its substrate, kinesin family member 3A (KIF3A). We also find that deletion of the CTD of CAPK compromises both localization to the primary cilium and negative regulation of ciliogenesis. Thus, CAPK substrate recognition, ciliary targeting, and ciliary function depend on the non-catalytic CTD of the protein which is predicted to be intrinsically disordered.

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Section: Introductionmentioning

confidence: 99%

Ciliopathy-Associated Protein Kinase ICK Requires Its Non-Catalytic Carboxyl-Terminal Domain for Regulation of Ciliogenesis

Wang

Gailey

et al. 2019

Cells

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“…Inactivation of IFT motor kinesin-2 in temperature sensitive mutants of Chlamydomonas induces deciliation as well as ciliary shortening [23,29,31]. Interestingly, acute ablation of kinesin-2 in mammalian induces ciliary disassembly mainly via deciliation [30]. It is not clear how inactivation of kinesin-2 triggers distinct modes of ciliary disassembly.…”

Section: Plos Geneticsmentioning

confidence: 99%

“…Intraflagellar transport (IFT) ferries ciliary proteins to build and maintain cilia [27,28]. Conditional inactivation of IFT motor kinesin-2 induces ciliary disassembly in both mammalian cells and in Chlamydomonas [23,[29][30][31], suggesting that cells may employ the mechanism of inactivation of IFT machinery to trigger ciliary disassembly. However, it has been shown that IFT proteins are actually increased in resorbing cilia upon cilia resorption that occurs during zygote development or in response to extracellular stimuli in Chlamydomonas [32,33], implying that IFT may be involved in ciliary resorption triggered by internal or external stimuli.…”

Section: Introductionmentioning

confidence: 99%

FLS2 is a CDK-like kinase that directly binds IFT70 and is required for proper ciliary disassembly in Chlamydomonas

Zhao

Shao

et al. 2020

PLoS Genet

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Intraflagellar transport (IFT) is required for ciliary assembly and maintenance. While disruption of IFT may trigger ciliary disassembly, we show here that IFT mediated transport of a CDK-like kinase ensures proper ciliary disassembly. Mutations in flagellar shortening 2 (FLS2), encoding a CDK-like kinase, lead to retardation of cilia resorption and delay of cell cycle progression. Stimulation for ciliary disassembly induces gradual dephosphorylation of FLS2 accompanied with gradual inactivation. Loss of FLS2 or its kinase activity induces early onset of kinesin13 phosphorylation in cilia. FLS2 is predominantly localized in the cell body, however, it is transported to cilia upon induction of ciliary disassembly. FLS2 directly interacts with IFT70 and loss of this interaction inhibits its ciliary transport, leading to dysregulation of kinesin13 phosphorylation and retardation of ciliary disassembly. Thus, this work demonstrates that IFT plays active roles in controlling proper ciliary disassembly by transporting a protein kinase to cilia to regulate a microtubule depolymerizer.

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“…Targeting KIF3A in anterograde IFT In primary cilia, IFT is a bi-directional system that consists of kinesin-mediated anterograde and dyneinmediated retrograde movement of cargos. IFT, especially anterograde, is critical for proper cilium formation and maintenance of the structure [49]. Knockdown of CILK1 accelerates anterograde IFT in the primary cilium, which may provide a possible explanation for CILK1 deficiency-induced cilium elongation [44].…”

Section: Cilk1 Targets In Signalling Pathwaysmentioning

confidence: 99%

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

Gailey

Wang

et al. 2019

FEBS Letters

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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.

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Acute Inhibition of Heterotrimeric Kinesin-2 Function Reveals Mechanisms of Intraflagellar Transport in Mammalian Cilia

Cited by 62 publications

References 67 publications

Ciliopathy-Associated Protein Kinase ICK Requires Its Non-Catalytic Carboxyl-Terminal Domain for Regulation of Ciliogenesis

Ciliopathy-Associated Protein Kinase ICK Requires Its Non-Catalytic Carboxyl-Terminal Domain for Regulation of Ciliogenesis

FLS2 is a CDK-like kinase that directly binds IFT70 and is required for proper ciliary disassembly in Chlamydomonas

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

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