肌醇多磷酸多激酶的PI3k活性丧失会损害PDK1介导的AKT激活、细胞迁移和肠道稳态。
Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis.
作者信息
Reilly Luke, Semenza Evan R, Koshkaryan George, Mishra Subrata, Chatterjee Sujan, Abramson Efrat, Mishra Pamela, Sei Yoshitasu, Wank Stephen A, Donowitz Mark, Snyder Solomon H, Guha Prasun
机构信息
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Nevada Institute of Personalized Medicine (NIPM), University of Nevada, Las Vegas, NV 89154, USA.
出版信息
iScience. 2023 Apr 11;26(5):106623. doi: 10.1016/j.isci.2023.106623. eCollection 2023 May 19.
Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK's) lipid kinase property drives AKT activation via increasing membrane localization and activation of PDK1 (3-Phosphoinositide-dependent kinase 1), largely independent of class I PI3k (cPI3K). Deletion of IPMK impairs cell migration, which is partially associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent myosin light chain (MLC) phosphorylation. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. In conclusion, the PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis.
蛋白激酶B（AKT）对细胞存活、增殖和迁移至关重要，并且与多种疾病相关。在此，我们证明肌醇多磷酸多激酶（IPMK）的脂质激酶特性通过增加膜定位和激活3-磷酸肌醇依赖性激酶1（PDK1）来驱动AKT激活，这在很大程度上独立于I类磷脂酰肌醇-3激酶（cPI3K）。IPMK的缺失会损害细胞迁移，这部分与PDK1介导的Rho相关卷曲螺旋形成蛋白激酶1（ROCK1）去抑制作用的消除以及随后肌球蛋白轻链（MLC）磷酸化有关。IPMK在肠道上皮细胞（IEC）中高表达。在IEC中删除IPMK会降低AKT磷酸化水平，并减少潘氏细胞数量。IPMK的缺失在基础状态以及化疗诱导损伤后均损害IEC再生，这表明IPMK在激活AKT和肠道组织再生中具有广泛作用。总之，IPMK的PI3K活性对于PDK-1介导的AKT激活和肠道稳态是必需的。
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