ADAM15

ADAM15 Full Name

ADAM metallopeptidase domain 15

ADAM15 Introduction

ADAM15, also known as MDC15 (metalloproteinase-like, disintegrin-like, cysteine-rich protein 15) or metargidin, is a member of the ADAM (a disintegrin and metalloproteinase) family of transmembrane proteins. The gene encoding ADAM15 is located on human chromosome 1q21.3, a region frequently associated with genomic alterations in various cancers. Unlike some ADAM family members that have lost catalytic activity, ADAM15 possesses a functional metalloprotease domain, making it an enzymatically active sheddase. ADAM15 is widely expressed in human tissues, including the heart, brain, placenta, lung, kidney, pancreas, and especially in vascular endothelial cells and smooth muscle cells. Its unique ability to bind integrins via its disintegrin loop and to cleave multiple cell-surface substrates positions ADAM15 as a key regulator of cell adhesion, migration, and signaling.

Figure 1. Many members of the M12 ADAM family of metallopeptidases are pseudopeptidases. (Lyons, Peter J, 2024)

Structural Domains of ADAM15
ADAM15 shares the canonical multidomain architecture of the ADAM family. From the N-terminus to the C-terminus, it contains: a signal peptide for secretion, a prodomain that maintains the enzyme in an inactive state (removed by furin-like convertases), a metalloprotease domain with the zinc-binding catalytic consensus sequence HEXXHXXGXXH, a disintegrin-like domain that mediates integrin recognition, a cysteine-rich domain, an EGF-like repeat, a transmembrane helix, and a cytoplasmic tail. A distinguishing feature of ADAM15 is its disintegrin loop which contains the tripeptide sequence RGD (arginine-glycine-aspartic acid) – the classical integrin-binding motif. This RGD motif is present in only a few ADAMs (ADAM15 and ADAM9 in some species) and allows ADAM15 to bind directly to integrins such as αvβ3, α5β1, and α9β1. The cytoplasmic tail of ADAM15 contains several potential phosphorylation sites and SH3-binding motifs (e.g., proline-rich regions), enabling interactions with intracellular signaling adaptors like Src family kinases and Grb2.

ADAM15 in Cancer: Tumor Suppressor or Oncogene?
ADAM15 plays a complex and context-dependent role in cancer biology. In several tumor types, including breast cancer, prostate cancer, and gastric cancer, ADAM15 expression is upregulated and correlates with poor prognosis, increased invasion, and metastasis. This pro-tumorigenic function is attributed to its ability to cleave cell adhesion molecules (e.g., E-cadherin), promote cell migration, and activate growth factor signaling through HB-EGF shedding. Conversely, in other contexts such as pancreatic cancer and certain glioma models, ADAM15 has been reported to suppress tumor growth and angiogenesis. This dual behavior may depend on the specific integrin partners, the cellular microenvironment, and the balance between its metalloprotease and adhesive functions. Notably, the RGD motif in ADAM15 allows it to competitively inhibit integrin-mediated cell adhesion, and overexpression of ADAM15 can reduce tumor cell attachment to extracellular matrix proteins, thereby either promoting or inhibiting metastasis depending on the stage of cancer progression.

Alternate Names for ADAM15

MDC15

• 1.Lyons, Peter J. Inactive metallopeptidase homologs: the secret lives of pseudopeptidases. Frontiers in Molecular Biosciences, 2024,11: 1436917.