Multiple non-catalytic ADAMs are novel integrin α4 ligands
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The ADAM (a disintegrin and metalloprotease) protein family uniquely exhibits both catalytic and adhesive properties. In the well-defined process of ectodomain shedding, ADAMs transform latent, cell-bound substrates into soluble, biologically active derivatives to regulate a spectrum of normal and pathological processes. In contrast, the integrin ligand properties of ADAMs are not fully understood. Emerging models posit that ADAM–integrin interactions regulate shedding activity by localizing or sequestering the ADAM sheddase. Interestingly, 8 of the 21 human ADAMs are predicted to be catalytically inactive. Unlike their catalytically active counterparts, integrin recognition of these “dead” enzymes has not been largely reported. The present study delineates the integrin ligand properties of a group of non-catalytic ADAMs. Here we report that human ADAM11, ADAM23, and ADAM29 selectively support integrin α4-dependent cell adhesion. This is the first demonstration that the disintegrin-like domains of multiple catalytically inactive ADAMs are ligands for a select subset of integrin receptors that also recognize catalytically active ADAMs.
KeywordsADAM Disintegrin Integrin Cell adhesion Lymphocyte
This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health and internal funds from the Arkansas College of Osteopathic Medicine and Brody School of Medicine at East Carolina University.
- 15.Verbisck NV, Costa ET, Costa FF, Cavalher FP, Costa MD, Muras A, Paixao VA, Moura R, Granato MF, Ierardi DF, Machado T, Melo F, Ribeiro KB, Cunha IW, Lima VC, Maciel Mdo S, Carvalho AL, Soares FF, Zanata S, Sogayar MC, Chammas R, Camargo AA (2009) ADAM23 negatively modulates alpha(v)beta(3) integrin activation during metastasis. Cancer Res 69:5546–5552. doi: 10.1158/0008-5472.CAN-08-2976 CrossRefPubMedGoogle Scholar
- 29.Long J, Li M, Ren Q, Zhang C, Fan J, Duan Y, Chen J, Li B, Deng L (2012) Phylogenetic and molecular evolution of the ADAM (A Disintegrin And Metalloprotease) gene family from Xenopus tropicalis, to Mus musculus, Rattus norvegicus, and Homo sapiens. Gene 507:36–43. doi: 10.1016/j.gene.2012.07.016 CrossRefPubMedGoogle Scholar
- 31.Liu H, Shim AH, He X (2009) Structural characterization of the ectodomain of a disintegrin and metalloproteinase-22 (ADAM22), a neural adhesion receptor instead of metalloproteinase: insights on ADAM function. J Biol Chem 284:29077–29086. doi: 10.1074/jbc.M109.014258 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Eto K, Huet C, Tarui T, Kupriyanov S, Liu HZ, Puzon-McLaughlin W, Zhang XP, Sheppard D, Engvall E, Takada Y (2002) Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions. J Biol Chem 277:17804–17810CrossRefPubMedGoogle Scholar