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First published online March 7, 2007
doi: 10.1242/10.1242/jcs.03403

Journal of Cell Science 120, 943-952 (2007)
Published by The Company of Biologists 2007
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Research Article

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

Nobuko Kawaguchi1, Keisuke Horiuchi2, J. David Becherer3, Yoshiaki Toyama2, Peter Besmer1,* and Carl P. Blobel4,5,*

1 Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
2 Department of Orthopedic Surgery, Keio University, School of Medicine, Tokyo 160-8582, Japan
3 Department of Biochemical and Analytical Pharmacology, GlaxoSmithKline Inc., Research Triangle Park, NC 27709, USA
4 Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA
5 Departments of Medicine and of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021, USA

* Authors for correspondence (e-mail: p-besmer{at}ski.mskcc.org; blobelc{at}hss.edu)

Accepted 10 January 2007

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.

Key words: Kit ligand, ADAM17, ADAM19, Ectodomain shedding




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