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

Yoon Seon Oh,Benjamin L Allen,Eric J Wang,David L Brautigan,Casey D Gailey,Zheng Fu

doi:10.3390/cells8070677

Yoon Seon Oh, Benjamin L Allen + Show 4 more

Open Access

https://doi.org/10.3390/cells8070677

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Journal: Cells	Publication Date: Jul 4, 2019
Citations: 31	License type: CC BY 4.0

Affiliation: University of Virginia, University of Michigan–Ann Arbor

Abstract

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.

Highlights

Intestinal cell kinase (ICK) is a highly conserved serine/threonine protein kinase in the CMGC (CDK/MAPK/GSK3/CLK) group of the human kinome [1,2]
We found that the long, unstructured, non-catalytic carboxyl-terminal domain (CTD) of CAPK is required for this interaction with and phosphorylation of kinesin family member 3A (KIF3A)
CAPK is very similar to classic MAPKs in the N-terminal catalytic domain, it diverges very similar tosequence classic MAPKs the N-terminal catalytic domain, diverges significantly in both isthe length and of theinC-terminal non-catalytic domain it(CTD)

Summary

Introduction

Intestinal cell kinase (ICK) is a highly conserved serine/threonine protein kinase in the CMGC (CDK/MAPK/GSK3/CLK) group of the human kinome [1,2]. Unlike classic MAPKs it is not acutely activated by growth factors through canonical dual-specificity upstream. ICK is activated by phosphorylation of Thr157 in its TDY motif by CDK20. (cyclin-dependent protein kinase 20) ( known as CCRK, cell cycle-related kinase) [4]. The tyrosine in this motif undergoes auto-phosphorylation for full activation of ICK [3]. In addition to the TDY motif regulation, ICK may be partially inactivated by fibroblast growth factor (FGF) signaling-mediated phosphorylation of the conserved Tyr15 [5]

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Conclusion