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

Abstract

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

• 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 18 Pg. 7036-41 (May 02 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16636290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ASAP1 protein, human
• Adaptor Proteins, Signal Transducing
• Benzaldehydes
• CTTN protein, human
• Cortactin
• Gene Products, tat
• Multiprotein Complexes
• Peptides
• UCS15A
• Proline

Topics

• Adaptor Proteins, Signal Transducing (chemistry, genetics, metabolism)
• Animals
• Benzaldehydes (metabolism)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cortactin (chemistry, genetics, metabolism)
• Female
• Gene Products, tat (genetics, metabolism)
• Humans
• Models, Molecular
• Molecular Structure
• Multiprotein Complexes
• Neoplasm Invasiveness (prevention & control)
• Neoplasm Metastasis (prevention & control)
• Peptides (genetics, metabolism)
• Proline (metabolism)
• Protein Binding
• Protein Conformation
• src Homology Domains