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Receptor activity modifying protein‐3 mediates the protumorigenic activity of lysyl oxidase‐like protein‐2
Author(s) -
Brekhman Vera,
Lugassie Jennie,
ZaffryarEilot Shelly,
Sabo Edmond,
Kessler Ofra,
Smith Victoria,
Golding Hana,
Neufeld Gera
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-162677
Subject(s) - lysyl oxidase , chemistry , receptor , autocrine signalling , cancer research , microbiology and biotechnology , biology , biochemistry , extracellular matrix
Lysyl oxidase‐like protein‐2 (LOXL2) induces epithelial to mesenchymal transition and promotes invasiveness. To understand the mechanisms involved, we examined the effect of LOXL2 overexpression in MCF‐7 cells on gene expression. We found that LOXL2 up‐regulated the expression of receptor activity modifying protein‐3 (RAMP3). Expression of RAMP3 in MDA‐MB‐231 cells in which LOXL2 expression was inhibited restored vimentin expression, invasiveness, and tumor development. Inhibition of RAMP3 expression in MDA‐MB‐231 cells mimicked the effects produced by inhibition of LOXL2expression and was accompanied by inhibition of p38 phosphorylation. LOXL2 overexpression in these cells did not restore invasiveness, suggesting that RAMP3 functions downstream to LOXL2. LOXL2 and RAMP3 are strongly coexpressed in human colon, breast, and gastric carcinomas but not in normal colon or gastric epithelial cells. RAMP3 associates with several G‐protein‐coupled receptors forming receptors for peptides, such as adrenomedullin and amylin. We hypothesized that RAMP3 could function as a transducer of autocrine signals induced by such peptides. However, the proinvasive effects of RAMP3 could not be abrogated following inhibition of the expression or activity of these peptides. Our experiments suggest that the protumorigenic effects of LOXL2 are partially mediated by RAMP3 and that RAMP3 inhibitors may function as antitumorigenic agents.—Brekhman, V., Lugassie, J., Zaffryar‐Eilot, S., Sabo, E., Kessler, O., Smith, V.,Golding, H., Neufeld, G. Receptor activity modifying protein‐3 mediates the protu‐morigenic activity of lysyl oxidase‐like protein‐2. FASEBJ. 25, 55–65 (2011). www.fasebj.org