芬兰图尔库大学Johanna Ivaska课题组揭示了整合素β1磷酸化的动态调控支持乳腺癌细胞的侵袭。这一研究成果于2025年5月26日发表在国际顶尖学术期刊《自然—细胞生物学》上。

在这里，该团队设计了一个荧光共振能量转移生物传感器，用于整合素β1磷酸化，筛选了96个蛋白酪氨酸磷酸酶，并确定了Shp2和PTP-PEST作为负调控因子来解决这一空白。整合素NPxY（783/795）位点的突变揭示了整合素磷酸化对有效癌细胞侵袭的重要性，这进一步得到了对已鉴定的整合素磷酸化调节因子Shp2和Src激酶的抑制的支持。利用蛋白质组学方法，研究人员发现Cofilin是磷酸化整合素- dok1复合体的一个组成部分，并将该轴与有效的侵入性形成联系起来，这是一个支持乳腺癌侵袭的过程。这些数据进一步表明，在转移传播的不同阶段，整合素β1磷酸化在NPxY位点的动态调节。

据了解，整合素是癌细胞和细胞外基质之间的重要桥梁，在疾病进展的每个阶段都起着核心作用。尽管人们认识到整合素磷酸化在几个生物过程中的重要性，但其调控机制及其相关性仍不清楚。

附：英文原文

Title: Dynamic regulation of integrin β1 phosphorylation supports invasion of breast cancer cells

Author: Conway, James R. W., Joshi, Omkar, Kaivola, Jasmin, Follain, Gautier, Gounis, Michalis, Khl, David, Ivaska, Johanna

Issue&Volume: 2025-05-26

Abstract: Integrins provide an essential bridge between cancer cells and the extracellular matrix, playing a central role in every stage of disease progression. Despite the recognized importance of integrin phosphorylation in several biological processes, the regulatory mechanisms and their relevance remained elusive. Here we engineer a fluorescence resonance energy transfer biosensor for integrin β1 phosphorylation, screening 96 protein tyrosine phosphatases and identifying Shp2 and PTP-PEST as negative regulators to address this gap. Mutation of the integrin NPxY(783/795) sites revealed the importance of integrin phosphorylation for efficient cancer cell invasion, further supported by inhibition of the identified integrin phosphorylation regulators Shp2 and Src kinase. Using proteomics approaches, we uncovered Cofilin as a component of the phosphorylated integrin-Dok1 complex and linked this axis to effective invadopodia formation, a process supporting breast cancer invasion. These data further implicate dynamic modulation of integrin β1 phosphorylation at NPxY sites at different stages of metastatic dissemination.

DOI: 10.1038/s41556-025-01663-4

Source: https://www.nature.com/articles/s41556-025-01663-4