Department of Molecular Biology and 2 Department of Radiation Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
J Cell Biol. 2012 Jun 25;197(7):983-96. doi: 10.1083/jcb.201201065.
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.
表皮生长因子受体 (EGFR) 信号转导是乳腺癌恶性的关键因素之一。乳腺癌细胞常过度表达 Arf6 及其效应物 AMAP1/ASAP1/DDEF1；在这些细胞中，EGFR 信号转导可能激活 Arf6 通路，诱导侵袭和转移。一些整合素的活跃循环对侵袭和转移至关重要。在这里，我们表明 Arf6-AMAP1 途径与回收β1 整合素（如α3β1）的机制相关，以促进 EGFR 刺激后的细胞侵袭。我们发现 AMAP1 能够直接结合 PRKD2，从而与β1 亚基的细胞质尾巴形成复合物。此外，GTP-Rab5c 也与 AMAP1 结合，EGFR 信号转导激活 Rab5c 对于促进 AMAP1 和 PRKD2 的细胞内关联是必要的。我们的结果表明了一种新的机制，即 EGFR 信号通过整合素循环促进某些乳腺癌细胞的侵袭性。
