Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis.
Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis.
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DOI：
10.1016/j.isci.2023.106623
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发表时间：
2023-05-19
期刊：
影响因子：
5.8
通讯作者：
Guha, Prasun
中科院分区：
文献类型：
--
作者：
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
蛋白激酶B（AKT）对于细胞存活、增殖和迁移是必需的，并且与多种疾病相关。在这里，我们证明了肌醇多磷酸多激酶（IPMK）的脂质激酶特性通过增加膜定位和PDK 1（3-磷酸肌醇依赖性激酶1）的激活来驱动AKT激活，这在很大程度上独立于I类PI 3 K（cPI 3 K）。IPMK的缺失损害细胞迁移，这部分与PDK 1介导的ROCK 1去抑制和随后的肌球蛋白轻链（MLC）磷酸化的消除有关。IPMK在肠上皮细胞（IEC）中高度表达。在IEC中删除IPMK减少了AKT磷酸化并减少了潘氏细胞的数量。IPMK的消融损害了IEC再生的基础和化疗诱导的损伤后，这表明IPMK在激活AKT和肠组织再生中的广泛作用。总之，IPMK的PI 3 k活性对于PDK 1介导的AKT活化和肠道内稳态是必需的。IPMK的PI 3 k活性对PDK 1膜定位至关重要IPMK对AKT活化至关重要IPMK对细胞迁移至关重要IPMK与肠道再生/潘氏细胞组织相关胃肠病学;分子生物学;细胞生物学
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. PI3k activity of IPMK is critical for PDK1 membrane localization IPMK is important for AKT activation IPMK is crucial for cell migration IPMK is linked to intestinal regeneration/Paneth cell organization Gastroenterology; Molecular biology; Cell biology
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影响因子：
8.8
作者：
Guha, Prasun;Tyagi, Richa;Snyder, Solomon H.
通讯作者：
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影响因子：
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Alzheimer’s Disease Neuroimaging Initiative
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影响因子：
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作者：
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影响因子：
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作者：
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