Kinase Family CDKL

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Kinase Classification: Group CMGC: Family CDKL

The CDKL (CDK-Like) family is very similar to CDK but are not known to interact with cyclins, and are distinct from CDKs and found in all eukaryotes other than fungi. Little is known of their function. Humans have 5 CDKLs (CDKL1-5), of which 1-4 are similar and 5 is distinctive in evolution and sequence.

Evolution

CDKL kinases are found in all eukaryotes examined to date other than fungi. CDKL1 and CDKL2 are similar and probably derive from an early vertebrate duplication; CDKL3 and CDKL4 are recent inventions, and are absent from fish; while CDKL5 has specific orthologs all the way back to early protist, but is absent from major models like Drosophila and C. elegans.

Domain Structure

CDKLs generally have a N-terminal kinase domain followed by a divergent sequence of up to several hundred AA without any other known domains.

Unlike their closest relatives, CDKs, all CDKL have TxY motif in their activation loop, like MAPK and RCK families. Phosphosite shows that the TxY tyrosine of CDKL5 is highly phosphorylated. Y262 is also heavily phosphorylated. It is conserved in CDKL5 homologs even in ciliates, but not in other CDKL. Phosphosite has no data for CDKL2-4. CDKL5 autophosphorylates on the TxY motif, as assayed by a cross-reacting anti-MAPK antibody; it's not clear which of the TxY residues are phosphorylated in this assay [1]. All CDKL also conserve the Y in the G-rich loop that is the Wee1 site equivalent in CDK1, but it has not been reported as phosphorylated.

Function

CDKL1 associates with TGFb pathway proteins TGFbR1 and SMURF1 in a targeted protein interaction screen [2], and may correlate with Drosophila CDKL being found in a TGFb pathway RNAi screen [3]. It is expressed selectively in glial cells of the brain [4], and was weakly associated with cognitive behavior in a GWAS study [5]. Zebrafish CDKL1 is expressed from fertilization onwards, and is particularly high in ovary, testis, and brain, and knockdown lead to brain and eye malformation, pericardial edema, and body axis curvature [6].

CDKL1 and CDKL2 were expressed in opposing reproductive tissues: Ovary for CDKL1 and Testis for CDKL2, and both were enzymatically activated by EGF stimulation, though this did not require TxY activation loop phosphorylation [7]. CDKL2 is expressed in various sets of brain neurons in mice [8][9] and expression is induced in rabbit brains during a learning test [10] and knockout mice also suggested a role in cognitive function [11]. Re-analysis of a breast cancer GWAS study also highlighted CDKL2, along with EPH receptors, as possible contributors to cancer [12].

CDKL3 is also expressed in CNS neurons, in a developmentally-regulated pattern [13]. Knockdown and overexpression in cultured cells suggested that it functions to increase dendrite growth and branching and to inhibit axonal growth. CDKL3 was linked to one case of mild mental retardation in which a translocation breakpoint was mapped to within CDKL3, resulting in a halving of expression level [14]. A kinome RNAi screen identified CDKL3 as a one of 9 suppressors of microautophagy [15], while overexpression of CDKL3 in cell lines resulted in increased proliferation [16].

CDKL4 has never been characterized. The human form contains a single AA change at a conserved arginine that is likely to reduce or eliminate kinase activity (this AA is conserved across all other CDKL) (Reuben Valas, Gerard Manning, unpublished).

The C. elegans CDKL5, Y42A5A.4, is not functionally annotated, but Drosophila CG7236 has a wealth of high-throughput data. RNAi knockdown in S2 and Kc cells show that knockdown induces multinucleate cells [17][18][19], a decreased mitotic index [17], and large cells or large nuclei [20]. In a screen of 3 hemocyte lines (S2, S2R+ and Kc), and three neuronal cells, CG7236 was expressed in all cells but had a phenotype only in the hemocyte lines.

In protein interaction screens, it shows an interaction with Cyclin K, suggesting that it might indeed be a cyclin-interacting class of kinases. In another RNAi screen, CG72336 caused a phenotype of large cells, large nuclei and multinucleate cells in 3 hemocyte cell lines (S2, S2R+ and Kc), but no phenotype in a trio of neuronal cell lines, despite being expressed in all cells [20]. CG72336 also emerged as one of 701 genes in a screen for JNK signaling [21], and as one of 346 genes that disrupted TGFb (dpp) signaling [3].

In Trypanosoma brucei, mutants the CDKL TbECK1 is expressed constitutively throughout the lifecycle and a truncation of the C-terminal tail induces a slow-growth phenotype [22]

References

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  1. Error fetching PMID 16935860: [Bertani]
  2. Error fetching PMID 15761153: [Barrios-Rodiles]
  3. Error fetching PMID 17785517: [Xu]
  4. Error fetching PMID 7595554: [Yen]
  5. Error fetching PMID 20125193: [Cirulli]
  6. Error fetching PMID 21747697: [Hsu]
  7. Error fetching PMID 9000130: [Taglienti]
  8. Error fetching PMID 10800923: [Sassa]
  9. Error fetching PMID 14605869: [Sassa2]
  10. Error fetching PMID 10531455: [Gomi]
  11. Error fetching PMID 20428496: [Gomi2]
  12. Error fetching PMID 20347982: [Liu2]
  13. Error fetching PMID 18412109: [Dubos]
  14. Error fetching PMID 21508686: [Szyniarowski]
  15. Error fetching PMID 17945021: [Jaluria]
  16. Error fetching PMID 15616552: [Bettencourt-Diaz]
  17. Error fetching PMID 14527345: [Kiger]
  18. Error fetching PMID 15380073: [Echard]
  19. Error fetching PMID 19265526: [Liu]
  20. Error fetching PMID 19893628: [Bond]
  21. Error fetching PMID 15387824: [Ellis]
  22. Error fetching PMID 21124932: [Boniface]
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