The Lymphocyte Metalloprotease MDC-L (ADAM 28) Is a Ligand for the Integrin α4β1

Abstract

A disintegrin and metalloprotease (ADAM) 1 is a family of recently identified cell surface and secreted glycoproteins that possess both proteolytic and adhesive properties (1, 2). Prototypical members of this family are composed of a prodomain, metalloprotease, disintegrin-like, cysteine-rich, EGF-like, transmembrane, and cytoplasmic domains. The metalloprotease domain is homologous to the reprolysins, members of the metazincin superfamily that include the matrix metalloproteases, the astacins, and serralysins (3). Although the ADAMs may serve other proteolytic functions, their role in the ectodomain shedding of specific cell surface proteins has been well documented (4, 5). ADAMs 9 (meltrin-␥), 10 (kuzbian), and 17 (tissue necrosis factor-␣-converting enzyme) have been shown to function in ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor, amyloid precursor protein, and tissue necrosis factor-␣, respectively (6 -10). These ADAMs and other members of this protein family have also been implicated in the shedding of other proteins such as L-selectin, FasL, and VCAM-1 (11-13). In addition to the proteolytic functions mentioned, several ADAMs have been shown to interact with the integrin family of cell surface receptors. Integrins are a widely distributed superfamily of noncovalent heterodimeric glycoproteins that play a vital role in cellular adhesion, migration, and signal transduction (14, 15). The ADAM disintegrin-like domains are homologous to small non-enzymatic peptides isolated from the venom of snakes that function as antagonists of integrins (16,17). The direct interaction of the snake venom disintegrin peptides with integrins led to the hypothesis that the disintegrin-like domains of ADAMs may function as integrin ligands. The disintegrin-like domains of ADAMs 1-3 expressed on the surface of sperm interact with the integrin ␣ 6 ␤ 1 in association with CD9 and CD98 on the egg surface (18 -23). Recognition of ADAMs 2 and 3 by ␣ 6 ␤ 1 requires the residues DECD located within a region of the disintegrin domain, designated the disintegrin loop, that corresponds to an extended loop in the snake venom peptides that typically contains an RGD sequence required for integrin binding (21-23). Human ADAM 15 contains an RGD sequence within the disintegrin loop region and is recognized by the integrins ␣ v ␤ 3 and ␣ 5 ␤ 1 (24 -26). However, mouse ADAM 15 lacks the RGD sequence found in the human homologue. Both human and mouse ADAM 15 as well as ADAM 12 were shown to be recognized by the integrin ␣ 9 ␤ 1 via residues outside the disintegrin loop (27). Other ADAM disintegrin-like domains reported to bind integrins are ADAM 9, which is recognized by ␣ 6 ␤ 1 and ␣ v ␤ 5 (28, 29), and ADAM 23, which is recognized by ␣ v ␤ 3 (30). * This work was supported by National Institutes of Health Grant AI47314. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section...

Human CD8+EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

“…ADAMs are regulatory proteins that pose both proteolytic activity and the ability to modulate intercellular adhesion. Indeed, as well as ADAM28's involvement in membrane‐bound TNF‐α cleavage (Jowett et al ., 2012), the disintegrin domain of ADAM28 also serves as a ligand for the integrin α4β1 (Bridges et al ., 2002). Therefore, the upregulation of proteases may also indicate changes to the migratory potential of the EMRA subset.…”

“…ADAMs (a disintegrin and metalloprotease) are a family of transmembrane proteins which control interactions with the extracellular matrix through proteolytic modification of cell surface proteins, as well as acting as adhesion molecules (Seals & Courtneidge, 2003). ADAM28 has been shown to be involved in membrane‐bound TNF‐α cleavage (Jowett et al ., 2012), as well as serving as a ligand for the integrin α4β1, where it is thought to target the active protease to substrates at the site of cell–cell contact (Bridges et al ., 2002). Additionally, ADAM28 has also been shown to bind P‐selectin glycoprotein ligand‐1 (PSGL‐1) enhancing cell adhesion to endothelial cells and subsequent migration into tissues (Shimoda et al ., 2007).…”

Next generation RNA‐sequencing in prognostic subsets of chronic lymphocytic leukemia

“…Recently, NOTCH1 and NOTCH2 mutations have been identified as recurrent events in CLL/Richter syndrome [17,18], indicating that aberrant NOTCH-signaling contributes to CLL development. Missense mutations in both ADAM28, which is involved in cell-cell interactions through ITGA4/ITGB1, [19] and CD45, a cell surface glycoprotein with tyrosine phosphatase activity crucial for activation of B cell lines [20], could also be confirmed at diagnosis (Fig. 2B), suggesting that these mutations are early events in CLL pathogenesis.…”

Gelatinase-mediated migration and invasion of cancer cells

“…The ADAMs have also been implicated as binding partners with integrins. For example, ADAM-28 interacts with α 4 β 1 integrin (Bridges et al, 2002), ADAM-15 binds to both α V β 3 and α 5 β 1 integrins (Nath et al, 1999) and TACE/ADAM-17 associates with α 5 β 1 integrin (Bax et al, 2004).…”

“…Other proteases than MMPs may also interact with integrins. These include uPA/uPAR, which may interact with several integrins (Aguirre Ghiso et al, 1999;Carriero et al, 1999;Wei et al, 2001;Wei et al, 1996;Xue et al, 1997), elastase with α M β 2 integrin (Cai and Wright, 1996), snake venom disintegrin/metalloproteinase with α 2 β 1 integrin (Ivaska et al, 1999) and ADAMs with several integrins (Bax et al, 2004;Bridges et al, 2002;Nath et al, 1999).…”