Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities.
Identification of the molecular machinery employed in cancer invasion, but not in normal adult cells, will greatly contribute to cancer therapeutics. Here we found that an ArfGAP, AMAP1/PAG2, is expressed at high levels in highly invasive breast cancer cells, but at very low levels in noninvasive breast cancer cells and normal mammary epithelial cells. siRNA-mediated silencing of AMAP1 effectively blocked the invasive activities. AMAP1 expression in human breast primary tumors also indicated its potential correlation with malignancy. Paxillin and cortactin have been shown to colocalize at invadopodia and play a pivotal role in breast cancer invasion. We found that AMAP1 is also localized at invadopodia, and acts to bridge paxillin and cortactin. This AMAP1-mediated trimeric protein complex was detected only in invasive cancer cells, and blocking this complex formation effectively inhibited their invasive activities in vitro and metastasis in mice. Our results indicate that AMAP1 is a component involved in invasive activities of different breast cancers, and provide new information regarding the possible therapeutic targets for prevention of breast cancer invasion and metastasis.
Onodera
Yasuhito
Y
Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka, Japan.
Hashimoto
Shigeru
S
Hashimoto
Ari
A
Morishige
Masaki
M
Mazaki
Yuichi
Y
Yamada
Atsuko
A
Ogawa
Eiji
E
Adachi
Masashi
M
Sakurai
Takaki
T
Manabe
Toshiaki
T
Wada
Hiromi
H
Matsuura
Nariaki
N
Sabe
Hisataka
H
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D051356:Cortactin; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics
C117891:ASAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C495868:CTTN protein, human; D051356:Cortactin; C495869:Cttn protein, mouse; D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; D034741:RNA, Small Interfering; D011392:Proline
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