Identification of H-Ras-Specific motif for the activation of invasive signaling program in human breast epithelial cells

Hae Young Yong, Jin Sun Hwang, Hwajin Son, Hae In Park, Eok Soo Oh, Hyun Hwi Kim, Do Kyun Kim, Wahn Soo Choi, Bong Jin Lee, Hyeong Reh Choi Kim, Aree Moon

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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.

Original languageEnglish
Pages (from-to)98-107
Number of pages10
Issue number2
StatePublished - Feb 2011

Bibliographical note

Funding Information:
Address all correspondence to: Dr. Aree Moon, College of Pharmacy, Duksung Women’s University, Seoul 132-714, South Korea. E-mail: 1This work was supported by the Korean Science and Engineering Foundation/ National Research Laboratory Program (MEST, no. ROA-2008-000-20070-0) and by the National Research Foundation of Korea (MEST, no. R11-20100001707). 2This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at Received 30 July 2010; Revised 5 November 2010; Accepted 15 November 2010 Copyright © 2011 Neoplasia Press, Inc. All rights reserved 1522-8002/11/$25.00 DOI 10.1593/neo.101088


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