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

作者：Kawahara Rebeca; Lima Renato Niyama; Domingues Romenia R; Pauletti Bianca Alves; Meirelles Gabriela V; Assis Michelle; Migliorini Figueira Ana Carolina; Paes Leme Adriana Franco

来源：Journal of Proteome Research, 2014, 13(4): 2080-2093.

DOI：10.1021/pr401224u

• ADAM17
• secretome
• label-free
• SILAC
• signaling
• proliferation
• migration

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 PPAR gamma downstream activation. These findings demonstrated fine-tuning of cell signaling rendered by the soluble molecules mediated by ADAM17.

• 出版日期2014-4