Identification of Dok-4b, a Dok-4 splice variant with enhanced inhibitory properties.
Dok adapter proteins have been primarily implicated in negative regulation of tyrosine kinase signaling, but Dok-4 has been reported to exert both inhibitory and stimulatory effects. We have identified a splice variant of Dok-4, Dok-4b, which contains a 39 aa insert within the its C-terminal region. The approximately 45kDa Dok-4b protein was detected in several human epithelial cell lines. Based on genomic sequences, Dok-4b was also predicted to exist in primates and possibly bovines, but not in rodents or other species. Compared to Dok-4, Dok-4b inhibited the tyrosine kinase-induced activation of both Erk and Elk-1 more strongly. Truncation of the C-terminal region of Dok-4 (Dok-4 DeltaCT) also enhanced the inhibitory activity of Dok-4, whereas expression of the isolated C-terminal domain enhanced Elk-1 activation, suggesting that the N-terminus and C-terminus of Dok-4 possess opposing inhibitory and stimulatory properties, respectively, the balance of which is altered by alternative splicing of Dok-4 to Dok-b.
Baldwin
Cindy
C
Department of Medicine, Division of Nephrology, McGill University Health Centre, Montreal, Que., Canada H3A 2B4.
Bedirian
Arda
A
Li
Hongping
H
Takano
Tomoko
T
Lemay
Serge
S
D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells; D014644:Genetic Variation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D011323:Primates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012377:Rodentia; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C486625:DOK4 protein, human; C494112:ELK1 protein, human; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D050807:ets-Domain Protein Elk-1; D011505:Protein-Tyrosine Kinases