GPCR Signaling Mediates Tumor Metastasis via PI3Kβ.
GPCR Signaling Mediates Tumor Metastasis via PI3Kβ.
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DOI：
10.1158/0008-5472.can-15-1675
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发表时间：
2016-05-15
期刊：
影响因子：
11.2
通讯作者：
Backer JM
中科院分区：
文献类型：
--
作者：
Khalil BD;Hsueh C;Cao Y;Abi Saab WF;Wang Y;Condeelis JS;Bresnick AR;Backer JM
PI 3 K信号传导的不适当激活与人类癌症密切相关。尽管关于PI 3 K信号在乳腺肿瘤发生和发展中的作用的研究主要集中在PI 3 K α上，但PI 3 K β的作用已经开始显现。PI 3 K β亚型在IA类PI 3 K酶中是独特的，因为它被受体酪氨酸激酶和G蛋白偶联受体（GPCR）激活。在以前的工作中，我们发现了一个特异性消除PI 3 K β与Gβγ结合的突变（p110526 KK-DD）。该突变体在p110β沉默的乳腺癌细胞中的表达抑制了体外和体内转移级联的多个步骤，并导致侵袭性伪足基质降解的细胞自主缺陷。我们的研究结果确定了GPCR和PI 3 K β在介导转移中的新联系，表明这种联系的破坏可能提供一种新的治疗靶点，以防止转移性疾病的发展。
Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Kα, a role for PI3Kβ has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein-coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolished PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCR and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease.