Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

Abstract

Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub-family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co-ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

Keywords: CLK; DYRK; HIPK; SRPK; differentiation; embryonic development; intellectual disability; kinase signalling; neurodevelopment; phosphorylation; stem cells.

Fig. 1

Phylogeny and features of the related SRPK, CLK, and DYRK kinase families. (A) A major branch of the CMGC kinase group contains the kinase families SRPK, CLK, DYRK, and the DYRK sub‐family HIPK. Figure reproduced from kinmap software [323] reproduced courtesy of Cell Signalling Technology, Inc. (www.cellsignal.com) (B) Schematic of the molecular features of human kinases with domains and key regulatory motifs indicated.

Fig. 2

Biochemical characteristics of the SRPK, CLK, and DYRK kinase families. Key structural features, motifs, and known substrates for the related SRPK, CLK, and DYRK kinase families and HIPK sub‐family. Lists of substrates typically refer to studies in mammalian systems except for HIPK, which includes direct substrates identified from Drosophila studies. PDB IDs: SRPK1 (1WAK), CLK1 (6KHD), DYRK1A (7AJ2), HIPK2 (7NCF) [10, 22, 23, 38, 39, 41, 42, 44, 57, 61, 63, 65, 75, 76, 80, 90, 91, 95, 99, 114, 128, 133, 136, 153, 159, 160, 162, 169, 183, 224, 227, 231, 239, 324, 325, 326, 327, 328]. Created with Biorender.com.

Fig. 3

Involvement of SRPK, CLK, and DYRK kinase families in neurodevelopmental and neurological disorders. Created with BioRender.com.