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局部合成的磷脂酰肌醇-3,4-二磷酸脂质驱动黏着斑周转。

Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover.

机构信息

UCL Cancer Institute, University College London, London WC1E 6DD, UK.

UCL Cancer Institute, University College London, London WC1E 6DD, UK.

出版信息

Dev Cell. 2022 Jul 25;57(14):1694-1711.e7. doi: 10.1016/j.devcel.2022.06.011. Epub 2022 Jul 8.

DOI:10.1016/j.devcel.2022.06.011
PMID:35809565
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7613278/
Abstract

Focal adhesions are multifunctional organelles that couple cell-matrix adhesion to cytoskeletal force transmission and signaling and to steer cell migration and collective cell behavior. Whereas proteomic changes at focal adhesions are well understood, little is known about signaling lipids in focal adhesion dynamics. Through the characterization of cells from mice with a kinase-inactivating point mutation in the class II PI3K-C2β, we find that generation of the phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P) membrane lipid promotes focal adhesion disassembly in response to changing environmental conditions. We show that reduced growth factor signaling sensed by protein kinase N, an mTORC2 target and effector of RhoA, synergizes with the adhesion disassembly factor DEPDC1B to induce local synthesis of PtdIns(3,4)P by PI3K-C2β. PtdIns(3,4)P then promotes turnover of RhoA-dependent stress fibers by recruiting the PtdIns(3,4)P-dependent RhoA-GTPase-activating protein ARAP3. Our findings uncover a pathway by which cessation of growth factor signaling facilitates cell-matrix adhesion disassembly via a phosphoinositide lipid switch.

摘要

焦点黏附是一种多功能细胞器，它将细胞-基质黏附与细胞骨架力传递和信号转导联系起来，并指导细胞迁移和细胞集体行为。虽然焦点黏附的蛋白质组变化已经得到很好的理解，但关于焦点黏附动力学中的信号脂质知之甚少。通过对具有 II 类 PI3K-C2β激酶失活点突变的小鼠细胞进行表征，我们发现产生磷脂酰肌醇-3,4-二磷酸（PtdIns(3,4)P）膜脂质可促进焦点黏附在环境条件变化时解聚。我们表明，蛋白激酶 N 感知到的生长因子信号减少，蛋白激酶 N 是 mTORC2 的靶标和 RhoA 的效应物，与黏附解聚因子 DEPDC1B 协同作用，诱导 PI3K-C2β 局部合成 PtdIns(3,4)P。然后，PtdIns(3,4)P 通过招募 PtdIns(3,4)P 依赖性 RhoA-GTPase 激活蛋白 ARAP3 促进 RhoA 依赖性应力纤维的周转。我们的发现揭示了一条途径，即生长因子信号的停止通过磷酸肌醇脂质开关促进细胞-基质黏附的解聚。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/edd1f1acf392/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/1c944ebd82fd/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/29dcb2b3f1ae/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/ca8a69e94889/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/fd48ed3a98a0/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/b2e21767ee53/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/822c648c1e9c/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/6b16fff42d15/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/edd1f1acf392/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/1c944ebd82fd/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/29dcb2b3f1ae/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/ca8a69e94889/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/fd48ed3a98a0/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/b2e21767ee53/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/822c648c1e9c/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/6b16fff42d15/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f439/9616723/edd1f1acf392/gr7.jpg

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