Roseman University of Health Sciences School of Pharmacy, 11 Sunset Way, Henderson, NV, 89014, USA.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Mol Cell Biochem. 2019 Nov;461(1-2):103-118. doi: 10.1007/s11010-019-03594-9. Epub 2019 Jul 30.
G protein-coupled receptor kinases (GRKs) phosphorylate the activated forms of G protein-coupled receptors (GPCRs), leading to receptor desensitization and internalization. In addition, GRKs can modify the activity of many non-GPCR-signaling pathways as well, controlling other cellular functions beyond that directly associated with a GPCR. In this report, we show that cervical cancer HeLa cells and breast cancer MDA MB 231 cells with reduced GRK5 expression display increased sensitivity to the apoptotic effects of paclitaxel (Taxol). This effect in cancer cells with low GRK5 levels could be because of blunted histone deacetylase 6 (HDAC6) activity that leads to an increase in α-tubulin acetylation levels, which augments paclitaxel sensitivity. We demonstrate that GRK5 and HDAC6 form a signaling complex in cells and in vitro. GRK5 phosphorylates HDAC6 at Ser-21 to promote its deacetylase activity. Therefore, the GRK5-HDAC6 interaction may contribute to paclitaxel resistance in cancer cells.
G 蛋白偶联受体激酶（GRKs）可磷酸化 G 蛋白偶联受体（GPCRs）的激活形式，导致受体脱敏和内化。此外，GRKs 还可以修饰许多非 GPCR 信号通路的活性，从而控制与 GPCR 直接相关的其他细胞功能。在本报告中，我们表明，GRK5 表达降低的宫颈癌 HeLa 细胞和乳腺癌 MDA MB 231 细胞对紫杉醇（Taxol）的凋亡作用更敏感。在 GRK5 水平较低的癌细胞中，这种效应可能是由于组蛋白去乙酰化酶 6（HDAC6）活性减弱，导致α-微管蛋白乙酰化水平增加，从而增强了紫杉醇的敏感性。我们证明，GRK5 和 HDAC6 在细胞内和体外形成信号复合物。GRK5 可在丝氨酸 21 位磷酸化 HDAC6，从而促进其去乙酰化酶活性。因此，GRK5-HDAC6 相互作用可能导致癌细胞对紫杉醇产生耐药性。
