Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover.
Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover.
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DOI：
10.1016/j.devcel.2022.06.011
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发表时间：
2022-07-25
影响因子：
11.8
通讯作者：
Vanhaesebroeck B
中科院分区：
文献类型：
--
作者：
Posor Y;Kampyli C;Bilanges B;Ganguli S;Koch PA;Wallroth A;Morelli D;Jenkins M;Alliouachene S;Deltcheva E;Baum B;Haucke V;Vanhaesebroeck B
粘着斑是一种多功能的细胞器，它将细胞与基质的粘附与细胞骨架的力传递和信号传导相结合，并引导细胞迁移和集体细胞行为。而蛋白质组学的变化在粘着斑是很好的理解，很少有人知道信号脂质粘着斑动力学。通过对II类PI 3 K-C2 β中具有激酶失活点突变的小鼠细胞的表征，我们发现磷脂酰肌醇-3，4-二磷酸（PtdIns（3，4）P2）膜脂质的产生促进了对变化的环境条件的粘着斑分解。我们发现，由蛋白激酶N（RhoA的mTORC 2靶点和效应器）感知的生长因子信号传导减少，与粘附拆卸因子DEPDC 1B协同作用，诱导PI 3 K-C2 β局部合成PtdIns（3，4）P2。然后，PtdIns（3，4）P2通过募集PtdIns（3，4）P2依赖性RhoA-GTP酶激活蛋白ARAP 3来促进RhoA依赖性应力纤维的周转。我们的研究结果揭示了一个途径，通过该途径生长因子信号的停止促进细胞-基质粘附解体通过磷脂酰肌醇脂质开关。由PI 3 K-C2 β产生的PtdIns（3，4）P2促进局灶性粘附解除PI 3 K-C2 β向粘附的募集通过PKN 2的磷酸化调节局部PtdIns（3，4）P2形成通过ARAP 3 GAP的募集使RhoA失活细胞-基质粘附的重塑对于发育和组织稳态至关重要。Posor，Kampyli等人显示磷脂酰肌醇-3，4-二磷酸（PtdIns（3，4）P2）膜脂质合成通过使RhoA小GTP酶失活而促进粘着斑的分解。这确定了一条途径，通过膜脂质开关将生长因子信号传导的停止与粘附解体联系起来。
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)P2) 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)P2 by PI3K-C2β. PtdIns(3,4)P2 then promotes turnover of RhoA-dependent stress fibers by recruiting the PtdIns(3,4)P2-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. PtdIns(3,4)P2 produced by PI3K-C2β promote focal adhesion disassembly PI3K-C2β recruitment to adhesions is regulated via phosphorylation by PKN2 Local PtdIns(3,4)P2 formation inactivates RhoA through recruitment of the ARAP3 GAP Remodeling of cell-matrix adhesions is crucial for development and tissue homeostasis. Posor, Kampyli et al. show that synthesis of the phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) membrane lipid promotes disassembly of focal adhesions by inactivating the RhoA small GTPase. This identifies a pathway that links cessation of growth factor signaling to adhesion disassembly through a membrane lipid switch.
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影响因子：
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通讯作者：
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