Targeting AMAP1 and cortactin binding bearing an atypical src homology 3/proline interface for prevention of breast cancer invasion and metastasis

• DOI: 10.1073/pnas.0509166103
• Publication Date: 2006-04-25T00:38:36Z
• Authors: Shigeru Hashimoto; Mayumi Hirose; Ari Hashimoto; Masaki Morishige; Atsuko Yamada; Harumi Hosaka; Ken-ichi Akagi; Eiji Ogawa; Chitose Oneyama; Tsutomu Agatsuma; Masato Okada; Hidenori Kobayashi; Hiromi Wada; Hirofumi Nakano; Takahisa Ikegami; Atsushi Nakagawa; Hisataka Sabe
• Keywords: Cortactin

Invasive potentials of carcinomas greatly contribute to their metastasis, which is a major threat in most cancers. We have recently shown that Arf6 plays pivotal role breast cancer invasive activities and identified AMAP1 as an effector GTP-Arf6 invasion. Expression correlates well with phenotypes primary tumors the human breast. also functions by forming trimeric protein complex cortactin paxillin. In this complex, binds src homology 3 (SH3) domain via its proline-rich peptide, SKKRPPPPPPGHKRT. SH3 domains are known bind generally ligands one-to-one stoichiometry. found AMAP1/cortactin binding very atypical stoichiometry interface structure, one peptide two simultaneously. made cell-permeable derived from we show specifically blocks binding, but not other canonical SH3/proline bindings, effectively inhibits invasion metastasis. Moreover, was block types cancers, such glioblastomas lung carcinomas. small-molecule compound, UCS15A, previously judged weak inhibitor against Together fine structural analysis, propose detected normal mammary epithelial cells, excellent drug target for therapeutics.