The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2.
Expression of the intracellular tyrosine kinase BRK/Sik is epithelial-specific and regulated during differentiation. Only a few substrates have been identified for BRK/Sik, including the KH domain containing RNA-binding protein Sam68 and the novel adaptor protein BKS. Although the physiological role of Sam68 is unknown, it has been shown to regulate mRNA transport, pre-mRNA splicing, and polyadenylation. Here we demonstrate that the Sam68-like mammalian proteins SLM-1 and SLM-2 but not the related KH domain containing heterogeneous nuclear ribonucleoprotein K are novel substrates of BRK/Sik. The expression of active BRK/Sik results in increased SLM-1 and SLM-2 phosphorylation and increased retention of BRK/Sik within the nucleus. The phosphorylation of SLM-1 and SLM-2 has functional relevance and leads to inhibition of their RNA-binding abilities. We show that SLM-1, SLM-2, and BRK/Sik have restricted patterns of expression unlike the ubiquitously expressed Sam68. Moreover, BRK/Sik, SLM-1, and Sam68 transcripts were coexpressed in the mouse gastrointestinal tract and skin, suggesting that SLM-1 and Sam68 could be physiologically relevant BRK/Sik targets in vivo. The ability of BRK/Sik to negatively regulate the RNA-binding activities of the KH domain RNA binding proteins SLM-1 and Sam68 may have an impact on the posttranscriptional regulation of epithelial cell gene expression.
Haegebarth
Andrea
A
Departments of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607, USA.
Heap
Darien
D
Bie
Wenjun
W
Derry
Jason J
JJ
Richard
Stéphane
S
Tyner
Angela L
AL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D004268:DNA-Binding Proteins; D004848:Epithelium / Q000737:chemistry; D005260:Female; D041981:Gastrointestinal Tract / Q000737:chemistry; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008321:Mammary Glands, Animal; D051379:Mice; D009363:Neoplasm Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D012313:RNA / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011993:Recombinant Fusion Proteins; D012867:Skin / Q000737:chemistry; D013379:Substrate Specificity; D013737:Testis / Q000737:chemistry; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; C513253:Khdrbs1 protein, mouse; C118776:Khdrbs2 protein, mouse; C486528:Khdrbs3 protein, mouse; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D012313:RNA; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; C000598269:Ptk6 protein, mouse; D019061:src-Family Kinases