title: Deciphering the role of the ADAM17-dependent secretome in cell signaling.
abstract: 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.
authors.affiliation: Laboratório Nacional de Biociências, LNBio, CNPEM, 13083-970 Campinas, Brazil.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Kawahara
authors.forename: Renato Niyama
authors.initials: RN
authors.lastname: Lima
authors.forename: Romênia R
authors.initials: RR
authors.lastname: Domingues
authors.forename: Bianca Alves
authors.initials: BA
authors.lastname: Pauletti
authors.forename: Gabriela V
authors.initials: GV
authors.lastname: Meirelles
authors.forename: Michelle
authors.initials: M
authors.lastname: Assis
authors.forename: Ana Carolina Migliorini
authors.initials: AC
authors.lastname: Figueira
authors.forename: Adriana Franco
authors.initials: AF
authors.lastname: Paes Leme
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D055786:Gene Knockout Techniques; D007553:Isotope Labeling; D051379:Mice; D020543:Proteome / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020543:Proteome; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse