Palmitoylation of the Alternative Amino Terminus of the BTK-C Isoform Controls Subcellular Distribution and Signaling
| Autor: | KOKABEE, MOSTAFA, WANG, XIANHUI, VOORAND, ELENA, ALIN, EDEN, KOKABEE, LEILA, KHAN, FAIZA, DESROSIERS, SOPHIA, CONKLIN, DOUGLAS S. |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Cancer Genomics Proteomics |
| ISSN: | 1790-6245 1109-6535 |
| Popis: | Background: The alternative transcriptional isoform of Bruton’s tyrosine kinase, BTK-C, is expressed in a wide variety of epithelial tumor types where it impacts apoptosis resistance, therapeutic escape, and glucose uptake. The initial exon in BTK-C encodes a 34 amino acid extension of the amino terminus of the canonical BTK-A isoform. Its function is unknown. Materials and Methods: Site-directed mutagenesis, acylation assays and expression studies in cancer cell lines were used to determine the effects that the BTK-C first exon sequence has on kinase activity, subcellular localization and cell physiology. Analysis of BTK-C expression in tumors was conducted using genomic databases. Results: BTK-C is palmitoylated on two cysteine residues. BTK-C localization at the plasma membrane is dependent upon phosphatidylinositol 3,4,5-triphosphate (PIP(3)) levels as well as palmitoylation. In epithelial cancer cells, both BTK-A and BTK-C isoforms are recruited to the plasma membrane; however, BTK-A also localizes to the nucleus whereas BTK-C has a primarily perinuclear distribution. Transcription of the BTK-C isoform is inversely correlated with expression of commonly activated breast cancer signaling receptors in breast tumors. In MDA-MB-231 cells, BTK-C expression confers modest increases in proliferation and glucose uptake rates compared to BTK-A. Conclusion: Palmitoylation affects localization and regulation of BTK-C in epithelial tumor cells where it functions as an important survival factor. Expression of either palmitoylated or non-palmitoylated kinase isoforms that function in PI3K signaling may be a common regulatory feature as nine other soluble kinases in the human genome possess similarly encoded alternative N-termini (ANT). |
| Databáze: | OpenAIRE |
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