Identification of H-Ras-Specific motif for the activation of invasive signaling program in human breast epithelial cells
- 설명문(URI) http://www.scopus.com/record/display.url?eid=2-s2.0-79951495657&origin=inward&txGid=BDAB39F0FE4C68BB27296C56EC605C0D.iqs8TDG0Wy6BURhzD3nFA%3a1
- 등재 SCIE, SCOPUS
- 발행기관 NEOPLASIA PRESS
- 발행년도 2011
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000091880
- 본문언어 영어
초록/요약
Increased expression and/or activation of H-Ras are often associated with tumor aggressiveness in breast cancer. Previously, we showed that H-Ras, but not N-Ras, induces MCF10A human breast epithelial cell invasion and migration, whereas both H-Ras and N-Ras induce cell proliferation and phenotypic transformation. In an attempt to determine the sequence requirement directing the divergent phenotype induced by H-Ras and N-Ras with a focus on the induction of human breast cell invasion, we investigated the structural and functional relationships between H-Ras and N-Ras using domain-swap and site-directed mutagenesis approaches. Here, we report that the hypervariable region (HVR), consisting of amino acids 166 to 189 in H-Ras, determines the invasive/migratory signaling program as shown by the exchange of invasive phenotype by swapping HVR sequences between H-Ras and N-Ras. We also demonstrate that the H-Ras-specific additional palmitoylation site at Cys184 is not responsible for the signaling events that distinguish between H-Ras and N-Ras. Importantly, this work identifies the C-terminal HVR, especially the flexible linker domain with two consecutive proline residues Pro173 and Pro174, as a critical domain that contributes to activation of H-Ras and its invasive potential in human breast epithelial cells. The present study sheds light on the structural basis for the Ras isoform-specific invasive program of breast epithelial cells, providing information for the development of agents that specifically target invasion-related H-Ras pathways in human cancer. © 2011 Neoplasia Press, Inc. All rights reserved.
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