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

Proceedings of the National Academy of Sciences of the United States of America
Shigeru HashimotoHisataka Sabe

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 lu...Continue Reading

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Citations

Feb 3, 2011·Amino Acids·Giuliano SiligardiArianna Donella-Deana
Mar 8, 2008·Clinical & Experimental Metastasis·Laura C KelleyScott A Weed
Feb 26, 2008·General Thoracic and Cardiovascular Surgery·Yataro Daigo, Yusuke Nakamura
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Oct 28, 2015·The Journal of Cell Biology·Valentina MarchesinPhilippe Chavrier
Apr 6, 2016·The Journal of Cell Biology·Ari HashimotoHisataka Sabe
Apr 8, 2016·The Journal of Organic Chemistry·Julien MalassisBruno Linclau
Mar 6, 2009·Cell Adhesion & Migration·Hisataka SabeEiji Ogawa
Jun 14, 2016·Cellular Logistics·Neeladri Sekhar RoyJames M Gruschus
Feb 13, 2014·Chemistry : a European Journal·Nathan BartlettBruno Linclau
Feb 9, 2016·Nature Communications·Shigeru HashimotoHisataka Sabe

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