Cooperative signaling between α6β4 integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion
Cooperative signaling between α6β4 integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion
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DOI：
10.1074/jbc.275.14.10604
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发表时间：
2000-04-07
影响因子：
4.8
通讯作者：
Falcioni, R
中科院分区：
文献类型：
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作者：
Gambaletta, D;Marchetti, A;Falcioni, R
我们先前的研究表明，整合素β(4)亚基的过表达增加了ErbB-2癌基因转化的NIH3T3细胞的体外侵袭力。我们使用这个模型来确定大的β(4)细胞质结构域中参与α(6)β(4)与ErbB-2的相互作用、侵袭和磷脂酰肌醇3-激酶(PI3K)激活的结构域。为此，我们在NIH3T3/ErbB-2细胞中表达了缺乏全部或部分β(4)细胞质结构域的β(4)缺失突变体。Me还使用了一个胞外结构域突变体，其中大部分β(4)的胞外结构域被c-Myc标签取代，这些转染体被检测了它们入侵Matrigel的能力和激活PI3K的能力，以及α(6)β(4)与ErbB-2共免疫沉淀的能力，结果表明，氨基酸854和1183之间的β(4)细胞质结构域的一个区域对于α(6)β(4)整合素增加侵袭的能力是关键的。有趣的是，β(4)的胞外区不是α(6)β(4)刺激侵袭所必需的。α(6)β(4)与ErbB-2的结合依赖于β(4)细胞质结构域，并且可以在没有α(6)β(4)异二聚化的情况下发生。最后，我们观察到PI3K与β(4)野生型和那些能够刺激NIH3T3/ErbB-2细胞侵袭的β(4)缺失突变体的强烈激活。总之，我们的结果证实了α(6)β(4)和ErbB-2在促进PI3K依赖的侵袭方面存在协同作用，并在这一事件中涉及β(4)细胞质区域(氨基酸854-1183)的特定区域。
We previously demonstrated that beta(4) integrin subunit overexpression increases in vitro invasiveness of NIH3T3 cells that have been transformed by ErbB-2 oncogene. We used this model to identify domains within the large beta(4) cytoplasmic domain that are involved in the interaction of alpha(6)beta(4) with ErbB-2, invasion, and phosphatidylinositol 3-kinase (PI3K) activation. For this purpose, we expressed deletion mutants of beta(4) that lacked either all or portions of the beta(4) cytoplasmic domain in NIH3T3/ErbB-2 cells. me also used an ecto-domain mutant in which most of the extracellular domain of beta(4) was replaced with a c-Myc tag, These transfectants were examined for their ability to invade Matrigel and their ability to activate PI3K, as well as for the ability of alpha(6)beta(4) to co-immunoprecipitate with ErbB-2, The results obtained revealed that a region of the beta(4) cytoplasmic domain between amino acids 854 and 1183 is critical for the ability of alpha(6)beta(4) integrin to increase invasion. Interestingly, the extracellular domain of beta(4) is not necessary for alpha(6)beta(4) to stimulate invasion. The association of alpha(6)beta(4) with ErbB-2 is dependent upon the beta(4) cytoplasmic domain and can occur in the absence of alpha(6)beta(4) heterodimerization, Finally, we observed strong activation of PI3K with beta(4) wild type and with those beta(4) deletion mutants that were able to stimulate invasion upon the expression in NIH3T3/ErbB-2 cells, In conclusion our results establish that there is cooperation between alpha(6)beta(4) and ErbB-2 in promoting PI3K-dependent invasion and implicate a specific region of the beta(4) cytoplasmic domain (amino acids 854-1183) in this event.