Rab5c promotes AMAP1-PRKD2 complex formation to enhance β1 integrin recycling in EGF-induced cancer invasion.
Rab5c promotes AMAP1-PRKD2 complex formation to enhance β1 integrin recycling in EGF-induced cancer invasion.
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DOI：
10.1083/jcb.201201065
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发表时间：
2012-06-25
期刊：
影响因子：
--
通讯作者：
Sabe H
中科院分区：
文献类型：
--
作者：
Onodera Y;Nam JM;Hashimoto A;Norman JC;Shirato H;Hashimoto S;Sabe H
EGF信号激活Rab 5c，促进AMAP 1和PRKD 2的细胞内结合，从而增强β1整合素再循环，促进乳腺癌细胞的侵袭力。表皮生长因子受体（EGFR）信号转导是乳腺癌恶性化的关键因素之一。乳腺癌细胞通常过表达Arf 6及其效应子AMAP 1/ASAP 1/DDEF 1;在这些细胞中，EGFR信号传导可激活Arf 6通路以诱导侵袭和转移。一些整合素的主动再循环对于侵袭和转移至关重要。在这里，我们发现Arf 6-AMAP 1通路与活化β1整联蛋白（如α3β1）的机制相关，从而在EGFR刺激下促进细胞侵袭。我们发现AMAP 1能够直接与PRKD 2结合，从而与β1亚基的胞质尾区形成复合物。此外，GTP-Rab 5c也与AMAP 1结合，EGFR信号传导激活Rab 5c对于促进AMAP 1和PRKD 2的细胞内结合是必要的。我们的研究结果提示了一种新的机制，EGFR信号通过整合素循环促进某些乳腺癌细胞的侵袭性。
EGF signaling activates Rab5c and promotes the intracellular association of AMAP1 and PRKD2 to enhance β1 integrin recycling and promote the invasiveness of breast cancer cells. Epidermal growth factor receptor (EGFR) signaling is one of the crucial factors in breast cancer malignancy. Breast cancer cells often overexpress Arf6 and its effector, AMAP1/ASAP1/DDEF1; in these cells, EGFR signaling may activate the Arf6 pathway to induce invasion and metastasis. Active recycling of some integrins is crucial for invasion and metastasis. Here, we show that the Arf6–AMAP1 pathway links to the machinery that recycles β1 integrins, such as α3β1, to promote cell invasion upon EGFR stimulation. We found that AMAP1 had the ability to bind directly to PRKD2 and hence to make a complex with the cytoplasmic tail of the β1 subunit. Moreover, GTP-Rab5c also bound to AMAP1, and activation of Rab5c by EGFR signaling was necessary to promote the intracellular association of AMAP1 and PRKD2. Our results suggest a novel mechanism by which EGFR signaling promotes the invasiveness of some breast cancer cells via integrin recycling.
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