Neuropilin-2 regulates α6β1 integrin in the formation of focal adhesions and signaling
Neuropilin-2 regulates α6β1 integrin in the formation of focal adhesions and signaling
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DOI：
10.1242/jcs.094433
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发表时间：
2012-01-15
影响因子：
4
通讯作者：
Mercurio, Arthur M.
中科院分区：
文献类型：
--
作者：
Goel, Hira Lal;Pursell, Bryan;Mercurio, Arthur M.
神经磷脂（NRPs）作为VEGF受体参与癌细胞的功能。考虑到NRP2在乳腺癌中被诱导并与侵袭性疾病相关，我们研究了NRP2在调节乳腺癌细胞与ECM相互作用中的作用。使用乳腺肿瘤上皮细胞，我们定义了NRP2（高）和NRP2（低）群体，它们在整合素表达和与层粘连蛋白的粘附方面存在差异。具体来说，NRP2（高）群体比NRP2（低）群体更强烈地粘附于层粘连蛋白，表达高水平的α 6 β 1整合素。NRP2（高）群体在层粘连蛋白上形成了许多局灶性粘连，这在NRP2（低）群体中没有看到。这些结果在表达NRP2和α 6 β 1整合素的乳腺癌细胞系中得到证实。耗尽实验表明，层粘连蛋白的粘附强度依赖于NRP2，而不依赖于胶原，并且层粘连蛋白需要VEGF。通过共免疫沉淀检测NRP2与α 6 β 1整合素之间的特异性相互作用。NRP2对于层粘连蛋白的黏附形成以及α 6 β 1整合素与细胞骨架的结合是必需的。NRP2还促进α 6 β 1整合素介导的FAK和Src的激活。出乎意料的是，我们发现NRP2位于层粘连蛋白的局灶粘连中。NRP2调节α 6 β 1整合素与层粘连蛋白相互作用形成局灶性粘连的机制涉及PKC激活。总之，我们的数据揭示了一个新的VEGF NRP2信号通路，激活α 6 β 1整合素并使其形成局灶粘连和信号。这一途径在乳腺癌的发病机制中很重要。
The neuropilins (NRPs) contribute to the function of cancer cells in their capacity as VEGF receptors. Given that NRP2 is induced in breast cancer and correlates with aggressive disease, we examined the role of NRP2 in regulating the interaction of breast cancer cells with the ECM. Using epithelial cells from breast tumors, we defined NRP2(high) and NRP2(low) populations that differed in integrin expression and adhesion to laminin. Specifically, the NRP2(high) population adhered more avidly to laminin and expressed high levels of the alpha 6 beta 1 integrin than the NRP2(low) population. The NRP2(high) population formed numerous focal adhesions on laminin that were not seen in the NRP2(low) population. These results were substantiated using breast carcinoma cell lines that express NRP2 and alpha 6 beta 1 integrin. Depletion experiments revealed that adhesive strength on laminin but not collagen is dependent on NRP2, and that VEGF is needed for adhesion on laminin. A specific interaction between NRP2 and alpha 6 beta 1 integrin was detected by co-immunoprecipitation. NRP2 is necessary for focal adhesion formation on laminin and for the association of alpha 6 beta 1 integrin with the cytoskeleton. NRP2 also facilitates alpha 6 beta 1-integrin-mediated activation of FAK and Src. Unexpectedly, we discovered that NRP2 is located in focal adhesions on laminin. The mechanism by which NRP2 regulates the interaction of alpha 6 beta 1 integrin with laminin to form focal adhesions involves PKC activation. Together, our data reveal a new VEGF NRP2 signaling pathway that activates the alpha 6 beta 1 integrin and enables it to form focal adhesions and signal. This pathway is important in the pathogenesis of breast cancer.