Rab5c promotes AMAP1-PRKD2 complex formation to enhance β1 integrin recycling in EGF-induced cancer invasion.
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.
Department of Molecular Biology and 2 Department of Radiation Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Yasuhito
Y
Onodera
Jin-Min
JM
Nam
Ari
A
Hashimoto
Jim C
JC
Norman
Hiroki
H
Shirato
Shigeru
S
Hashimoto
Hisataka
H
Sabe
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C117891:ASAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D019012:Integrin beta1; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C427755:RAB5C protein, human; D020696:rab5 GTP-Binding Proteins