Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK.
Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK.
复制标题
DOI：
10.1016/j.jbc.2022.101916
复制
发表时间：
2022-06
影响因子：
4.8
通讯作者：
Owen, Darerca
中科院分区：
文献类型：
--
作者：
Clayton, Natasha S.;Fox, Millie;Vicente-Garcia, Jose J.;Schroeder, Courtney M.;Littlewood, Trevor D.;Wilde, Jonathon, I;Krishnan, Kadalmani;Brown, Murray J. B.;Crafter, Claire;Mott, Helen R.;Owen, Darerca
活化的CDC42相关蛋白(ACK)是一种致癌的非受体酪氨酸激酶，与多种人类癌症的预后不良有关。ACK促进增殖，部分是通过激活Akt，Akt是1A型磷脂酰肌醇3-激酶(PI3Ks)的主要效应者，通过膜磷脂转导信号。我们现在表明，ACK还与1A类PI3K信号的其他关键组成部分，即PI3K调节亚基相互作用。我们证明ACK与所有五种PI3K调节亚基结合，并直接磷酸化Tyr607(或类似残基)上的p85α、p85β、p50α和p55α。我们发现p85β的磷酸化促进了HEK293T细胞的增殖。我们证明了ACK与p85α仅在核浓缩细胞组分中相互作用，其中p85α在Tyr607处磷酸化(PTyr607)也存在，并确定了pTyr607与支持调节亚单位二聚化的N-末端SH2结构域之间的相互作用。我们由此推断，ACK以p110非依赖的P85为靶标，并进一步假设这些调节亚单位二聚体承担支持ACK活性的新的核功能。我们的结论是，这些二聚体代表了一种先前未描述的对1A型PI3K调节亚单位的调节模式，并可能揭示治疗干预的其他途径。
Activated Cdc42-associated kinase (ACK) is an oncogenic nonreceptor tyrosine kinase associated with poor prognosis in several human cancers. ACK promotes proliferation, in part by contributing to the activation of Akt, the major effector of class 1A phosphoinositide 3-kinases (PI3Ks), which transduce signals via membrane phosphoinositol lipids. We now show that ACK also interacts with other key components of class 1A PI3K signaling, the PI3K regulatory subunits. We demonstrate ACK binds to all five PI3K regulatory subunit isoforms and directly phosphorylates p85α, p85β, p50α, and p55α on Tyr607 (or analogous residues). We found that phosphorylation of p85β promotes cell proliferation in HEK293T cells. We demonstrate that ACK interacts with p85α exclusively in nuclear-enriched cell fractions, where p85α phosphorylated at Tyr607 (pTyr607) also resides, and identify an interaction between pTyr607 and the N-terminal SH2 domain that supports dimerization of the regulatory subunits. We infer from this that ACK targets p110-independent p85 and further postulate that these regulatory subunit dimers undertake novel nuclear functions underpinning ACK activity. We conclude that these dimers represent a previously undescribed mode of regulation for the class1A PI3K regulatory subunits and potentially reveal additional avenues for therapeutic intervention.
登录
查看更多内容
通过p85α单体二聚体平衡对PI3K途径进行调节。
影响因子：
7.7
作者：
Cheung LW;Walkiewicz KW;Besong TM;Guo H;Hawke DH;Arold ST;Mills GB
通讯作者：
Mills GB
影响因子：
5
作者：
Honorato RV;Koukos PI;Jiménez-García B;Tsaregorodtsev A;Verlato M;Giachetti A;Rosato A;Bonvin AMJJ
通讯作者：
Bonvin AMJJ
DOI：
10.1073/pnas.0700420104
发表时间：
2007-05-15
影响因子：
11.1
作者：
Mahajan, Nupam P.;Liu, Yuanbo;Whang, Young E.
通讯作者：
Whang, Young E.
DOI：
10.1073/pnas.0908899107
发表时间：
2010-03-23
影响因子：
11.1
作者：
Chagpar, Ryaz B.;Links, Philip H.;Anderson, Deborah H.
通讯作者：
Anderson, Deborah H.
影响因子：
64.8
作者：
MANSER, E;LEUNG, T;LIM, L
通讯作者：
LIM, L