Metastasis-associated C4.4A, a GPI-anchored protein cleaved by ADAM10 and ADAM17.
Metalloproteases play a complex role in tumor progression. While the activity of some ADAM, ADAMTS and matrix metalloproteases (MMPs) seems to be protumorigenic, the activity of others seems to prevent tumor progression. The identification of the array of substrates of a given metalloprotease (degradome) seems an adequate approach to predict the effect of the inhibition of a metalloprotease in tumors. Here, we present the proteomic identification of a novel substrate for ADAM10 and -17. We used SILAC (Stable Isotope Labeling by Amino acids in Cell culture), a proteomic technique based on the differential metabolic labeling of cells in different conditions. This was applied to MCF7 cells derived from an invasive mammary tumor, and the same cells expressing shRNAs that knock down ADAM10 or -17. Following this approach, we have identified C4.4A as a substrate to both metalloproteases. Since C4.4A is likely involved in tumor invasion, these results indicate that the cleavage of C4.4A by ADAM10 and ADAM17 contributes to tumor progression.
Esselens
Cary W
CW
Medical Oncology Research Program, Vail d'Hebron University Hospital Research Institute, Psg. Vail d'Hebron 119-129, Universitat Autonoma de Barcelona, E-08035 Barcelona, Spain.
Malapeira
Jordi
J
Colomé
Núria
N
Moss
Marcia
M
Canals
Francesc
F
Arribas
Joaquín
J
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D040901:Proteomics; D013379:Substrate Specificity
D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C472589:LYPD3 protein, human; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human