Different ADAMs have distinct influences on Kit ligand processing: Phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19

Nabuko Kawaguchi, Keisuke Horiuchi, J. David Becherer, Yoshiaki Toyama, Peter Besmer, Carl P. Blobel

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)943-952
Number of pages10
JournalJournal of Cell Science
Volume120
Issue number6
DOIs
Publication statusPublished - 2007 Mar 15

Keywords

  • ADAM17
  • ADAM19
  • Ectodomain shedding
  • Kit ligand

ASJC Scopus subject areas

  • Cell Biology

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