dual specificity protein kinase CLK2; CDC-like kinase 2 (CLK2)

Function: - dual specificity protein kinase - phosphorlates both Ser/Thr & Tyr-containing substrates - phosphorylates Ser- & Arg-rich (SR) proteins of the spliceosomal complex - may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing - role in redistribution of SR proteins from nuclear speckles to a diffuse nucleoplasmic distribution - acts as a suppressor of hepatic gluconeogenesis & glucose secretion by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation - phosphorylates PPP2R5B thus stimulating assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1 - phosphorylates PTPN1, SRSF1 & SRSF3 - regulates alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells - autophosphorylates on Ser, Thr & Tyr - phosphorylation on Ser-34 & Thr-127 by AKT1 is induced by ionizing radiation or insulin - phosphorylation plays a critical role in cell proliferation following low dose radiation & prevents cell death following high dose radiation - phosphorylation at Thr-344 by PKB/AKT2 induces its kinase activity which is required for its stability. - phosphorylation status at Ser-142 influences its subnuclear localization - inhbition of phosphorylation at Ser-142 results in accumulation in nuclear speckles - interacts with RBMX - interacts with AKT1 & UBL5 Inhibition: - 5,6-dichloro-1-b-D-ribofuranosylbenzimidazole (DRB) inhibits CLK2 autophosphorylation - TG003 inhibits CLK2 kinase activity & affects the regulation of alternative splicing mediated by phosphorylation of SR proteins (putative) Structure: - belongs to the protein kinase superfamily, CMGC Ser/Thr protein kinase family, lammer subfamily - contains 1 protein kinase domain Compartment: - isoform 1: - nucleus, nuclear speckle - inhbition of phosphorylation at Ser-142 results in accumulation in nuclear speckles (putative) - isoform 2: - nuclear speckle - colocalizes with Ser- & Arg-rich (SR) proteins in the nuclear speckles Alternative splicing: - named isoforms=3 - at least one isoform lacks the kinase domain - at least one isoform may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay Expression: endothelial cells

General

nuclear protein protein kinase CLK (cdc-like kinase)

Properties

SIZE: entity length = 499 aa MW = 60 kD COMPARTMENT: cell nucleus MOTIF: Tyr phosphorylation site {Y7} Ser phosphorylation site {S34} Ser phosphorylation site {S50} Tyr phosphorylation site {Y51} Ser phosphorylation site {S83} Ser phosphorylation site {S98} Tyr phosphorylation site {Y99} Ser phosphorylation site {S106} Thr phosphorylation site {T127} Ser phosphorylation site {S142} Tyr phosphorylation site {Y153} kinase domain SITE: 163-479 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 169-177 Ser phosphorylation site {S167} ATP-binding site NAME: ATP-binding site SITE: 193-193 aspartate residue {D290} Thr phosphorylation site {T344} Ser phosphorylation site {S493} STATE: active state

Database Correlations

OMIM 602989 UniProt P49760 Pfam PF00069 Entrez Gene 1196 Kegg hsa:1196 ENZYME 2.7.12.1

References

UniProt :accession P49760