The Role of ADAM 15 in Glomerular Mesangial Cell Migration

Abstract

Mesangial cells (MC) occupy the core of the renal glomerulus and are surrounded by a mesangial matrix. In certain diseases, MC migrate through this matrix into the pericapillary space. The mechanisms involved, however, are poorly understood. Members of the ADAM (A Disintegrin And Metalloproteinase) family of membrane proteins have the potential to be key modulators of cellmatrix interactions through the activities of their constituent domains. We have studied the possible role of ADAM 15 in human (H) MC migration in vitro. HMC ADAM 15 was expressed at low levels in serum-free medium but was increased during migration. Antibodies to the individual domains of ADAM 15 and the incorporation of antisense ADAM 15, (but not control oligonucleotide) inhibited this migration. Furthermore, inhibition of migration by the broad spectrum metalloproteinase inhibitor BB3103, demonstrated that metalloproteinase activity was essential for migration. ADAM 15, extracted from HMC membranes, was an active metalloproteinase, which degraded both type IV collagen and gelatin prepared from fibrillar collagen. Activity was inhibited by EDTA but not by phenylmethylsulfonyl fluoride. This is the first report of the potential of ADAM 15 for involvement in the restructuring of the mesangial matrix and in the migration of MC in disease.Mesangial cell migration through the mesangial matrix and into the pericapillary space is a feature of a number of renal diseases, including mesangiocapillary glomerulonephritis (1). In addition, it appears that extracellular matrix components such as fibronectin (2), thrombospondin (3), and heparin-like glycosaminoglycans (4) can modulate this migration. This movement of cells must involve disengagement from and remodeling of the surrounding extracellular matrix. Possible mediators for this remodeling include a variety of serine proteinases and matrix metalloproteinases (MMPs) 1 but also the newly described ADAM family of molecules.The ADAMs are a family of cell surface molecules that possess both disintegrin and MMP domains. The disintegrin domain of these molecules resembles the sequence of the snake venom disintegrins and binds to integrins on the cell surface (5). This displaces the integrin from its matrix target, thus freeing the cell from its substrate. Moreover the binding of a disintegrin to integrins on its own cell membrane in addition to those on adjacent cells is a possibility, freeing both cells from their substratum. Furthermore, because the ADAM molecules are proteolytically processed (6), cleavage of the ADAM may also take place, releasing the bound disintegrin from the cell and freeing the cell from the matrix. In addition, the binding of the disintegrin domain to integrins on adjacent cells may direct the MMP to the site of integrin/matrix interaction resulting in matrix degradation and facilitating cell migration.The deduced structure of the MMP catalytic domain appears functional in many of the 30 or more ADAM family members (that is, there is an active site consensus sequence) (7), wher...

Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma

“…This isoform also decreased cell attachment, which may contribute to the lower Matrigel invasion capabilities of ADAM-15B -expressing cells compared with the ADAM-15A cells. There is substantial evidence that ADAM-15 can influence both cell adhesion and migration (31,36,37). Interactions of ADAM-15 disintegrin domain with integrins a v h 3 , a 5 h 1 , and a 9 h 1 have been documented (5)(6)(7), and these may in principle occur either in trans, regulating cell-cell adhesion, or in cis, thereby modulating cell interactions with matrix substrata.…”

ADAM 12 Cleaves Extracellular Matrix Proteins and Correlates with Cancer Status and Stage

“…This is an interesting finding given that proteases that degrade ECM components have been implicated in tumor growth and invasion as a function of their ability to degrade the basement membrane. Several other members of the ADAM family including ADAM 10, ADAM 15, and the closely related snake venom metalloprotease have been reported to have type IV collagen-and gelatin-degrading properties (21)(22)(23). Recently ADAM 13 has been reported to cleave fibronectin (24).…”

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

“…The metalloprotease domain of ADAMs has been shown to induce ectodomain shedding (a specialized type of limited proteolysis) of various membrane-bound proteins (e.g., cytokines and growth factors, cytokine and growth factor receptors, and adhesion molecules) in vitro and in vivo, whereas the disintegrin and cysteine-rich domains have adhesive properties in that they interact with integrins on the opposing cell surface (Seals and Courtneidge, 2003;White, 2003). Selected ADAM proteins have also been reported to degrade ECM proteins (Millichip et al, 1998;Alfandari et al, 2001;Martin et al, 2002;White, 2003) to facilitate cell migration. On the other hand, the cytoplasmic tails are divergent and contain several potential phosphorylation sites, as well as binding sites for Src homology region 3 domain-containing proteins (Seals and Courtneidge, 2003), which may ultimately regulate the ability of an ADAM to cleave a specific substrate.…”