Src stimulates fibroblast growth factor receptor-2 shedding by an ADAM15 splice variant linked to breast cancer.
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 cell-based assays compared with ADAM15A, which lacks a Src-binding 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 Src-kinase inhibitors and in Src(-/-) cells, but not in Src(-/-) 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.
Maretzky
Thorsten
T
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, and Department of Physiology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Le Gall
Sylvain M
SM
Worpenberg-Pietruk
Susanne
S
Eder
Jörg
J
Overall
Christopher M
CM
Huang
Xin-Yun
XY
Poghosyan
Zaruhi
Z
Edwards
Dylan R
DR
Blobel
Carl P
CP
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D020134:Catalytic Domain / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016391:Genes, src / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D008565:Membrane Proteins; D020033:Protein Isoforms; D051497:Receptor, Fibroblast Growth Factor, Type 2; D015688:Oncogene Protein pp60(v-src); D051722:ADAM Proteins; C098660:ADAM15 protein, human