Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461.
Mol Biol Cell. 2019 Aug 15;30(18):2367-2376. doi: 10.1091/mbc.E19-03-0182. Epub 2019 Jul 18.
The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously reported that the PI3Kβ isoform of PI 3-kinase, which is regulated by both receptor tyrosine kinases and G protein-coupled receptors, is required for invasion and gelatin degradation in breast cancer cells. We have now defined the mechanism by which PI3Kβ regulates invadopodia. We find that PI3Kβ is specifically activated downstream from integrins, and is required for integrin-stimulated spreading and haptotaxis as well as integrin-stimulated invadopodia formation. Surprisingly, these integrin-stimulated and PI3Kβ-dependent responses require the production of PI(3,4)P by the phosphoinositide 5'-phosphatase SHIP2. Thus, integrin activation of PI3Kβ is coupled to the SHIP2-dependent production of PI(3,4)P which regulates the recruitment of PH domain-containing scaffolds such as lamellipodin to invadopodia. These findings provide novel mechanistic insight into the role of PI3Kβ in the regulation of invadopodia in breast cancer cells.
肿瘤细胞从原发性肿瘤的侵袭是由入侵足介导的，入侵足是富含肌动蛋白的突起细胞器，可分泌基质金属蛋白酶并降解细胞外基质。这种突起活动与基质降解之间的偶联促进了肿瘤的侵袭。我们之前曾报道过，PI3-激酶的 PI3Kβ 同工型受受体酪氨酸激酶和 G 蛋白偶联受体调节，是乳腺癌细胞侵袭和明胶降解所必需的。我们现在已经确定了 PI3Kβ 调节入侵足的机制。我们发现 PI3Kβ 特异性地在整合素下游被激活，并且需要整合素刺激的扩展和趋化性以及整合素刺激的入侵足形成。令人惊讶的是，这些整合素刺激和 PI3Kβ 依赖性反应需要磷酸肌醇 5′-磷酸酶 SHIP2 产生 PI(3,4)P。因此，整合素激活 PI3Kβ 与 SHIP2 依赖性 PI(3,4)P 的产生偶联，调节 PH 结构域包含支架如 lamellipodin 向入侵足的募集。这些发现为 PI3Kβ 在调节乳腺癌细胞中入侵足方面的作用提供了新的机制见解。
