Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India; Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India.
Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, Telangana, India.
Drug Discov Today. 2022 Oct;27(10):103317. doi: 10.1016/j.drudis.2022.07.002. Epub 2022 Jul 11.
That reversible protein phosphorylation by kinases and phosphatases occurs in metabolic disorders is well known. Various studies have revealed that a multi-faceted and tightly regulated phosphatase, pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP)-1/2 displays robust effects in cardioprotection, ischaemia/reperfusion (I/R), and vascular remodelling. PHLPP1 promotes foamy macrophage development through ChREBP/AMPK-dependent pathways. Adipocyte-specific loss of PHLPP2 reduces adiposity, improves glucose tolerance,and attenuates fatty liver via the PHLPP2-HSL-PPARα axis. Discoveries of PHLPP1-mediated insulin resistance and pancreatic β cell death via the PHLPP1/2-Mst1-mTORC1 triangular loop have shed light on its significance in diabetology. PHLPP1 downregulation attenuates diabetic cardiomyopathy (DCM) by restoring PI3K-Akt-mTOR signalling. In this review, we summarise the functional role of, and cellular signalling mediated by, PHLPPs in metabolic tissues and discuss their potential as therapeutic targets.
蛋白激酶和磷酸酶介导的蛋白质可逆磷酸化在代谢紊乱中很常见。多项研究表明，多功能且受严格调控的磷酸酶——pleckstrin homology 结构域富含亮氨酸重复蛋白磷酸酶（PHLPP）-1/2 在心脏保护、缺血/再灌注（I/R）和血管重塑中具有显著作用。PHLPP1 通过 ChREBP/AMPK 依赖性途径促进泡沫巨噬细胞的发展。脂肪细胞特异性敲除 PHLPP2 通过 PHLPP2-HSL-PPARα 轴减少肥胖、改善葡萄糖耐量和减轻脂肪肝。通过 PHLPP1/2-Mst1-mTORC1 三角环发现 PHLPP1 介导的胰岛素抵抗和胰岛β细胞死亡，揭示了其在糖尿病学中的重要性。PHLPP1 下调通过恢复 PI3K-Akt-mTOR 信号通路来减轻糖尿病心肌病（DCM）。在这篇综述中，我们总结了 PHLPP 在代谢组织中的功能作用和细胞信号转导，并讨论了它们作为治疗靶点的潜力。
