Cancer Research Center and Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, NY, U.S.A.
Cancer Genomics Proteomics. 2022 Jul-Aug;19(4):415-427. doi: 10.21873/cgp.20329.
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.
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.
BTK-C is palmitoylated on two cysteine residues. BTK-C localization at the plasma membrane is dependent upon phosphatidylinositol 3,4,5-triphosphate (PIP) 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.
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).
布鲁顿酪氨酸激酶的替代转录异构体 BTK-C 在广泛的上皮肿瘤类型中表达，它影响细胞凋亡抵抗、治疗逃逸和葡萄糖摄取。BTK-C 的初始外显子编码经典 BTK-A 异构体氨基末端的 34 个氨基酸延伸。其功能未知。
使用定点突变、酰化测定和癌细胞系表达研究来确定 BTK-C 第一外显子序列对激酶活性、亚细胞定位和细胞生理学的影响。使用基因组数据库分析肿瘤中的 BTK-C 表达。
BTK-C 在两个半胱氨酸残基上发生棕榈酰化。BTK-C 在质膜上的定位取决于磷脂酰肌醇 3,4,5-三磷酸 (PIP) 水平以及棕榈酰化。在上皮癌细胞中，BTK-A 和 BTK-C 异构体都被募集到质膜；然而，BTK-A 还定位于细胞核，而 BTK-C 主要分布在核周。BTK-C 异构体的转录与乳腺癌中常见激活的信号受体的表达呈负相关。在 MDA-MB-231 细胞中，与 BTK-A 相比，BTK-C 表达使增殖和葡萄糖摄取率适度增加。
棕榈酰化影响上皮肿瘤细胞中 BTK-C 的定位和调节，它是一种重要的生存因子。在 PI3K 信号通路中发挥作用的棕榈酰化或非棕榈酰化激酶异构体的表达可能是一个常见的调节特征，因为人类基因组中的另外九个可溶性激酶具有类似编码的替代 N 末端 (ANT)。
