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

Title
Identification of H-Ras-Specific motif for the activation of invasive signaling program in human breast epithelial cells
Authors
Yong H.-Y.Hwang J.-S.Son H.Park H.-I.Oh E.-S.Kim H.-H.Kim D.K.Choi W.S.Lee B.-J.Kim H.-R.C.Moon A.
Ewha Authors
오억수
SCOPUS Author ID
오억수scopus
Issue Date
2011
Journal Title
Neoplasia
ISSN
1522-8002JCR Link
Citation
vol. 13, no. 2, pp. 98 - 107
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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.
DOI
10.1593/neo.101088
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자연과학대학 > 생명과학전공 > Journal papers
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