Different ADAMs have distinct influences on Kit ligand processing: Phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19 Journal Article
| Authors: | Kawaguchi, N.; Horiuchi, K.; Becherer, J. D.; Toyama, Y.; Besmer, P.; Blobel, C. P. |
| Article Title: | Different ADAMs have distinct influences on Kit ligand processing: Phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19 |
| Abstract: | Kit ligand (Kitl), the ligand for the Kit receptor tyrosine kinase, plays important roles in hematopoiesis, gametogenesis and melanogenesis. Kitl is synthesized as a membrane-anchored precursor that can be processed to produce the soluble growth factor. Here, we evaluated the role of ADAM (a disintegrin and metalloprotease) metalloproteases in ectodomain shedding of Kitl. We found that both ADAM17 and ADAM19 affect Kitl1 shedding, albeit in different ways. Overexpression of ADAM19 resulted in decreased levels of Endo-H-resistant mature Kitl1, thereby reducing the amount of Kitl that is shed from cells following stimulation with phorbol esters. ADAM17 was identified as the major phorbol-ester-stimulated sheddase of Kitl1, whereas ADAMS 8, 9, 10, 12 and 15 were not required for this process. ADAM17 also emerged as the major constitutive and phorbol-ester-stimulated sheddase of Kitl2 in mouse embryonic fibroblasts. Mutagenesis of the juxtamembrane domain of Kitl2 showed no stringent sequence requirement for cleavage by ADAM17, although two nonadjacent stretches of four amino acid residues were identified that are required for Kitl2 shedding. Taken together, this study identifies a novel sheddase, ADAM17, for Kitl1 and Kitl2, and demonstrates that ADAM19 can reduce ADAM17-dependent phorbol-ester-stimulated Kitl1 ectodomain shedding. |
| Keywords: | controlled study; protein expression; unclassified drug; nonhuman; protein domain; animal cell; mouse; animals; mice; cells, cultured; stem cell factor; embryo; enzyme degradation; protein protein interaction; enzyme activity; cercopithecus aethiops; cos cells; protein processing; amino acid sequence; molecular sequence data; protein processing, post-translational; membrane protein; alternative splicing; fibroblast; protein structure, tertiary; cell stimulation; site directed mutagenesis; genetic code; protein determination; metalloproteinase; adam protein; adam proteins; ectodomain shedding; phorbol ester; embryo cell; protein adam10; tetradecanoylphorbol acetate; protein precursors; protein adam8; adam17; adam19; kit ligand; a disintegrin and metalloprotease 10 protein; a disintegrin and metalloprotease 12 protein; a disintegrin and metalloprotease 15 protein; a disintegrin and metalloprotease 19 protein; a disintegrin and metalloprotease 8 protein; a disintegrin and metalloprotease 9 protein; protein adam12; protein adam15; protein adam19; protein adam9; protein kitl1; protein kitl2; stem cell factor 1 protein; stem cell factor 2 protein; tumor necrosis factor alpha converting enzyme |
| Journal Title: | Journal of Cell Science |
| Volume: | 120 |
| Issue: | 6 |
| ISSN: | 0021-9533 |
| Publisher: | Company of Biologists |
| Date Published: | 2007-03-15 |
| Start Page: | 943 |
| End Page: | 952 |
| Language: | English |
| DOI: | 10.1242/jcs.03403 |
| PUBMED: | 17344430 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 25" - "Export Date: 17 November 2011" - "CODEN: JNCSA" - "Source: Scopus" |
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