Deciphering the Role of the ADAM17-Dependent Secretome in Cell Signaling

ADAM17
has been initially identified as the main sheddase responsible for
releasing the soluble form of a variety of cell-surface proteins,
including growth factors, cytokines, cell adhesion molecules, and
receptors, most of which are associated with pathological processes,
including cancer and inflammation. However, the function and composition
of the ADAM17-dependent secretome on a proteome-wide scale is poorly
understood. In this study, we observed that the ADAM17-dependent secretome
plays an important role in promoting cell proliferation and migration.
To further demonstrate the repertoire of proteins involved in this
cross-talk, we employed mass-spectrometry-based proteomics using nonmetabolic
and metabolic labeling approaches to explore the secretome composition
of wild-type and ADAM17–/– knockout mouse
embryonic fibroblast (mEF) cells. Bioinformatic analyses indicated
the differential regulation of 277 soluble proteins in the ADAM17-dependent
secretome as well as novel direct ADAM17 cleavage substrates, such
as mimecan and perlecan. Furthermore, we found that the ADAM17-dependent
secretome promoted an opposite regulation of ERK and FAK pathways
as well as PPARγ downstream activation. These findings demonstrated
fine-tuning of cell signaling rendered by the soluble molecules mediated
by ADAM17.