High impact information on CLK1

• Through extensive screening of a chemical library, we found that a benzothiazole compound, TG003, had a potent inhibitory effect on the activity of Clk1/Sty [1].
• This drug also suppressed serine/arginine-rich protein phosphorylation, dissociation of nuclear speckles, and Clk1/Sty-dependent alternative splicing in mammalian cells [1].
• To study the role of tyrosines in the phosphorylation of STY protein kinase, four conserved tyrosine residues were sequentially substituted with phenylalanine and expressed as histidine fusion proteins [2].
• We recently reported that Arachis hypogaea serine/threonine/tyrosine (STY) protein kinase is developmentally regulated and is induced by abiotic stresses (Rudrabhatla, P., and Rajasekharan, R. (2002) Plant Physiol. 130, 380-390) [2].
• These findings suggest that the NH(2)-terminal region of hPRP4 may play regulatory roles under an unidentified signal transduction pathway through Clk1 [3].

Biological context of CLK1

• CLK1 phosphorylation of YPTP1 led to a 3-fold stimulation of phosphatase activity in vitro [4].
• The eukaryotic LAMMER protein kinase family is encoded by at least three loci in the human genome, designated CLK1, 2, and 3 [5].
• The suppressed genes include mainly cell cycle regulators like cyclin B1, cyclin H and kinases like c-abl, CLK1 and others [6].
• The suppressing mutation maps to the 3' end of a gene, masK, in an operon immediately upstream of the mglBA operon. masK encodes a protein of the STY kinase family [7].
• However, the actual cellular mechanism that regulates cell growth, differentiation, and development by CLK/STY remains unclear [8].

Anatomical context of CLK1

• CLK1 mRNA is expressed at low levels in all tissues and cell lines examined [9].
• STY is a murine LAMMER kinase which has been implicated in the control of PC12 cell differentiation [10].
• We have compared the expression patterns of these proteins in mouse tissues and transformed cell lines with that of a previously cloned family member (mCLK1/STY), and detected various transcripts for each gene [11].
• The deduced amino acid sequence and the data from immunostaining of CL-K1 cDNA expressing CHO cells revealed that CL-K1 is expressed as a secreted protein [12].

Associations of CLK1 with chemical compounds

• CROP was phosphorylated by mSRPK1, mSRPK2, and Clk1 in vitro, and when cells were treated with cisplatin the subnuclear distribution of GFP-CROP was changed [13].
• Tyrosine phosphorylation has been proposed to be critical for CLK1 activity, however, CLK1 activity was unaffected by exposure to tyrosine phosphatases [9].
• CLK1 activity is positively regulated by phosphorylation on either tyrosine residues or serine/threonine residues, and is negatively regulated by steric constraints mediated by the N-terminal domain, as well as, by phosphorylation on a subset of serine/threonine residues within the catalytic domain [9].
• Treatment of CLK1 with the serine/threonine specific phosphatase PP2A, resulted in a 2- to 6-fold increase in enzymatic activity [9].
• The ratio of the two splice variants of CLK1 can be altered by treatment with cycloheximide [9].

Regulatory relationships of CLK1

• These findings demonstrate that the CLK kinases activate PTP-1B family members, and this phosphatase may be an important cellular target for CLK action [4].

Other interactions of CLK1

• Co-expression of CLK1 or CLK2 with PTP-1B in HEK 293 cells led to a 2-fold stimulation of phosphatase activity in vivo [4].
• Enzymes that phosphorylate the SR proteins belong to the family of CDC2/CDC28-like kinases (CLK) [14].
• A benzothiazole compound TG003, a kinase inhibitor that targets Clk1 and Clk4, suppressed dissociation of nuclear speckles, altered the splicing patterns, and rescued the embryonic defects induced by excessive Clk activity [15].

Analytical, diagnostic and therapeutic context of CLK1

• Both immunofluorescence and transmission electron microscopy analyses of cells overexpressing Clk/STY indicate that IGC components are completely redistributed to a diffuse nuclear localization, leaving no residual structure [16].
• Recombinant STY protein kinase occurs as a monomer in solution as shown by gel filtration chromatography [17].
• The gene, called clk1 (Colletotrichum lindemuthianum kinase 1), was weakly expressed in the mycelium of the wild-type strain grown on rich and minimal synthetic media but was undetectable during the infection even when a sensitive reverse transcriptase-polymerase chain reaction methodology was used [18].
• CL-K1 is found in blood by immunoblotting and partial amino acid analyses [12].

References