RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms.
RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms.
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DOI：
10.1016/j.cell.2013.04.031
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发表时间：
2013-05-23
期刊：
影响因子：
64.5
通讯作者：
Downward J
中科院分区：
文献类型：
--
作者：
Fritsch R;de Krijger I;Fritsch K;George R;Reason B;Kumar MS;Diefenbacher M;Stamp G;Downward J
RAS蛋白是p110α、p110γ和p110δ I型磷酸肌醇3-激酶（PI 3 Ks）的重要直接激活剂，通过氨基末端RAS结合结构域（RBD）相互作用。在这里，我们研究了PI 3 K的普遍存在的p110β亚型的调节，涉及G蛋白偶联受体（GPCR）信号传导，PTEN丢失驱动的癌症和血小板功能。出乎意料的是，RAS不能与p110β相互作用，而是来自小GTP酶RHO亚家族的RAC 1和CDC 42通过其RBD结合并激活p110β。在成纤维细胞中，GPCR通过Dock 180/Elmo 1介导的RAC激活和随后与p110β的相互作用与PI 3 K偶联。携带p110β RBD突变的小鼠细胞显示PI 3 K活性降低和趋化性缺陷，这些小鼠对实验性肺纤维化具有抗性。这些发现通过表明RAS和RHO家族GTP酶直接调节不同的普遍存在的PI 3 K亚型以及RAC激活GPCR下游的p110β，修改了我们对I型PI 3 K调节的理解。与p110α、p110γ和p110δ PI 3 K亚型不同，RAS不能与p110β相互作用RHO家族GTP酶RAC 1和CDC 42通过其RBD GPCR直接结合并激活p110β，所述RBD GPCR通过Dock 180/Elmo 1偶联至PI 3 K。RBD突变型p110 β小鼠对实验性肺纤维化具有抗性RAS蛋白结合并激活多种PI 3 K同种型。然而，PI 3 K的p110β亚型反而通过RHO家族成员RAC和CDC 42的结合而被激活。阻断这种相互作用会减弱GPCR介导的细胞趋化性并赋予对肺纤维化的抗性。
RAS proteins are important direct activators of p110α, p110γ, and p110δ type I phosphoinositide 3-kinases (PI3Ks), interacting via an amino-terminal RAS-binding domain (RBD). Here, we investigate the regulation of the ubiquitous p110β isoform of PI3K, implicated in G-protein-coupled receptor (GPCR) signaling, PTEN-loss-driven cancers, and thrombocyte function. Unexpectedly, RAS is unable to interact with p110β, but instead RAC1 and CDC42 from the RHO subfamily of small GTPases bind and activate p110β via its RBD. In fibroblasts, GPCRs couple to PI3K through Dock180/Elmo1-mediated RAC activation and subsequent interaction with p110β. Cells from mice carrying mutations in the p110β RBD show reduced PI3K activity and defective chemotaxis, and these mice are resistant to experimental lung fibrosis. These findings revise our understanding of the regulation of type I PI3K by showing that both RAS and RHO family GTPases directly regulate distinct ubiquitous PI3K isoforms and that RAC activates p110β downstream of GPCRs. Unlike p110α, p110γ, and p110δ PI3K isoforms, RAS is unable to interact with p110β The RHO family GTPases RAC1 and CDC42 directly bind and activate p110β via its RBD GPCRs couple to PI3K via Dock180/Elmo1-mediated RAC activation and binding to p110β Mice with RBD mutant p110β are resistant to experimental lung fibrosis RAS proteins bind and activate multiple PI3K isoforms. The p110β isoform of PI3K, however, is instead activated by the binding of RHO family members RAC and CDC42. Blocking this interaction blunts GPCR-mediated cellular chemotaxis and confers resistance to lung fibrosis.
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影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
21.3
作者：
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通讯作者：
Vuori, K
影响因子：
64.5
作者：
Knight, Zachary A.;Gonzalez, Beatriz;Shokat, Kevan M.
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Shokat, Kevan M.
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Ciraolo E;Iezzi M;Marone R;Marengo S;Curcio C;Costa C;Azzolino O;Gonella C;Rubinetto C;Wu H;Dastrù W;Martin EL;Silengo L;Altruda F;Turco E;Lanzetti L;Musiani P;Rückle T;Rommel C;Backer JM;Forni G;Wymann MP;Hirsch E
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5.3
作者：
Rodriguez-Viciana, P;Sabatier, C;McCormick, F
通讯作者：
McCormick, F