The α and β Subunits of the Metalloprotease Meprin Are Expressed in Separate Layers of Human Epidermis, Revealing Different Functions in Keratinocyte Proliferation and Differentiation

Abstract

The zinc endopeptidase meprin (EC 3.4.24.18) is expressed in brush border membranes of intestine and kidney tubules, intestinal leukocytes, and certain cancer cells, suggesting a role in epithelial differentiation and cell migration. Here we show by RT-PCR and immunoblotting that meprin is also expressed in human skin. As visualized by immunohistochemistry, the two meprin subunits are localized in separate cell layers of the human epidermis. Meprin alpha is expressed in the stratum basale, whereas meprin beta is found in cells of the stratum granulosum just beneath the stratum corneum. In hyperproliferative epidermis such as in psoriasis vulgaris, meprin alpha showed a marked shift of expression from the basal to the uppermost layers of the epidermis. The expression patterns suggest distinct functions for the two subunits in skin. This assumption is supported by diverse effects of recombinant meprin alpha and beta on human adult low-calcium high-temperature keratinocytes. Here, beta induced a dramatic change in cell morphology and reduced the cell number, indicating a function in terminal differentiation, whereas meprin alpha did not affect cell viability, and may play a role in basal keratinocyte proliferation.

Meprinα Transactivates the Epidermal Growth Factor Receptor (EGFR) via Ligand Shedding, thereby Enhancing Colorectal Cancer Cell Proliferation and Migration

“…Additionally, meprin␣ and ␤ exhibit remarkable differences in their activation (46) and regulation by inhibitors (52) (Jefferson et al 62). This certainly contributes to the different functions in cell proliferation and migration as observed previously (40). In the large intestine, only minor amounts of meprin␤ are expressed.…”

“…Horseradish peroxidase-linked anti-rabbit and anti-mouse secondary antibodies were obtained from Dako Cytomation (Denmark). Recombinant active human meprin␣ and recombinant human pro-meprin␣ were generated using a baculovirus expression system in insect cells as previously described (39,40).…”

“…Nonactive pro-meprin␣ showed only a very slight increase in phosphorylation of the EGFR. Minor amounts of pro-meprin␣ might be activated over time, for instance by plasmin or kallikreins (KLKs) (40,46). Treatment with recombinant EGF resulted in a similar EGFR activation pattern to meprin␣ albeit with a stronger signal, which may have been due to the relatively high concentration of EGF used.…”

ADAM10 Is the Major Sheddase Responsible for the Release of Membrane-associated Meprin A

“…Expression of meprins has also been identified in human skin epithelia (2), leukocytes in the lamina propria of the human inflamed bowel (3,4), mesenteric lymph nodes (5), colorectal (3,4) and breast cancer cells (6), and recently in glomeruli of some strains of rat (7). Meprins are oligomeric neutral metalloproteinases composed of two evolutionarily related subunits, ␣ and ␤, that form homo-or hetero-oligomeric structures (1,8,9).…”

“…The role of meprin A has been studied in experimental models of acute kidney injury (AKI) 2 including ischemia-reperfusion (IR) and cisplatin nephrotoxicity. Meprin A-deficient mice were markedly resistant to IR injury, and a selective meprin A inhibitor provided protection from AKI induced by IR injury (13), cisplatin nephrotoxicity (14), and sepsis (15).…”