Src Stimulates Fibroblast Growth Factor Receptor-2 Shedding by an ADAM15 Splice Variant Linked to Breast Cancer

Abstract

ADAMs (a disintegrin and metalloproteinase) have important roles in development and diseases such as cancer. Previously, an ADAM15 splice variant (ADAM15B), which contains an inserted cytoplasmic Src-binding site, was linked to clinical aggressiveness in breast cancer, yet little was known about how this splice variant affects the function of ADAM15. Here, we show that ADAM15B has enhanced catalytic activity in cellbased assays compared with ADAM15A, which lacks a Srcbinding site, using shedding of fibroblast growth factor receptor 2iiib variant as an assay for catalytic activity. Moreover, the enhanced activity of ADAM15B compared with ADAM15A depends on Src because it is abolished by Srckinase inhibitors and in Src À/À cells, but not in Src À/À cells rescued with Src. These findings provide insights into the mechanism of how a splice variant linked to clinical agressiveness in breast cancer causes increased activity of ADAM15B, and suggest that inhibitors of the ADAM15 protease activity or of the interaction of ADAM15B with Src could be useful to treat breast cancer in patients with dysregulated ADAM15B. [Cancer Res 2009;69(11):4573-6]

ADAM9 silencing inhibits breast tumor cells transmigration through blood and lymphatic endothelial cells

“…ADAM9 also efficiently degraded several other extracellular matrix (ECM) proteins besides laminin, including fibronectin, entactin and insoluble elastin, in a model of acute lung injury [28]. In our experimental model, silencing of ADAM9 significantly decreased ADAM15 expression, and it is known that one of the variants of ADAM15 is related to greater catalytic activity, resulting in more aggressive breast tumors [29]. Therefore, we hypothesize that the silencing of ADAM9 decreases transendothelial migration properties of MDA-MB-231 cells through a direct (inhibition of cell-cell adhesion) and indirect mechanisms (inhibition of matrix degradation due to decreased activity of both ADAM9 and ADAM15).…”

The Cell to Cell Interaction of Breast Cancer Cells Regulates Cancer Invasion via Adam15

“…3D and E). It is known that cytoplasmic tail of phosphorylated ADAM15 interacts with Src (Maretzky et al, 2009;Poghosyan et al, 2002), which is up-stream to MEK1/2 (Guo and Giancotti, 2004), leading to Erk1/2 signaling pathway (Sun et al, 2010). In this study, phosphorylation of Erk was not affected by the cell to cell interaction via ADAM15 and integrins ( Fig.…”

“…The ADAM15 molecule consists of various domains with proteinase and integrin binding activities (Daugimont et al, 2011;Hart et al, 2005;Maretzky et al, 2009;Najy et al, 2008b;Ohtsu et al, 2006;TrochonJoseph et al, 2004;Wu et al, 2008;Zhong et al, 2008). One of the reason for exhibiting complex functions of ADAM15 might be due to its ability to interact with various integrins, leading to the distinct intracellular signaling.…”

ADAM15 Protein Amplifies Focal Adhesion Kinase Phosphorylation under Genotoxic Stress Conditions

“…It represents the major form (ϳ90%) expressed in a variety of tissues (29). Other splice variants are of low abundance (0.2-10%) (30) and were linked to aggressive forms of breast cancer (8,10). In our experimental setting, camptothecin, a DNA damage-promoting topoisomerase I inhibitor, was applied to induce apoptosis in the chondrocytic cell line T/C28a4, transfected either with full-length ADAM15 or the deletion mutant ADAM15⌬cyto (21).…”