Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation.
Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation.
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DOI：
10.1371/journal.pone.0009646
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发表时间：
2010-03-19
期刊：
影响因子：
3.7
通讯作者：
Mahajan NP
中科院分区：
文献类型：
--
作者：
Mahajan K;Coppola D;Challa S;Fang B;Chen YA;Zhu W;Lopez AS;Koomen J;Engelman RW;Rivera C;Muraoka-Cook RS;Cheng JQ;Schönbrunn E;Sebti SM;Earp HS;Mahajan NP
AKT/PKB激酶是癌症中最频繁激活的途径之一的关键信号传导组分，并且是癌症药物开发的主要靶标。大多数研究集中在其通过受体酪氨酸激酶（RTK）介导的磷脂酰肌醇-3-OH激酶（PI 3 K）激活或磷酸酶和张力蛋白同源物（PTEN）的丧失而激活。我们已经发现，生长因子与RTK结合导致非受体酪氨酸激酶Ack 1（也称为ACK或TNK 2）的激活，其直接磷酸化激酶结构域中进化上保守的酪氨酸176处的AKT。Tyr 176-磷酸化的AKT定位于质膜并促进Thr 308/Ser 473-磷酸化，导致AKT活化。在前列腺中特异性表达活化的Ack 1的小鼠表现出AKT Tyr 176-磷酸化，并发生小鼠前列腺上皮内瘤变（mPIN）。此外，Tyr 176-磷酸化-AKT和Tyr 284-磷酸化-Ack 1的表达水平与疾病进展的严重程度呈正相关，与乳腺癌患者的生存率呈负相关。因此，RTK/Ack 1/AKT通路为药物发现提供了新的靶点。
The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery.
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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.
影响因子：
4
作者：
Huang, Haojie;Tindall, Donald J.
通讯作者：
Tindall, Donald J.
影响因子：
64.8
作者：
MANSER, E;LEUNG, T;LIM, L
通讯作者：
LIM, L
影响因子：
4.8
作者：
Kiyono, M;Kato, J;Satoh, T
通讯作者：
Satoh, T
影响因子：
64.8
作者：
BURGERING, BMT;COFFER, PJ
通讯作者：
COFFER, PJ