ADAM10 Is the Constitutive Functional Sheddase of CD44 in Human Melanoma Cells

Abstract

CD44 proteins are cell surface receptors for hyaluronic acid (HA), a component of the extracellular matrix that has multiple effects on cell behavior. CD44 can be shed from the cell surface by proteolytic cleavage. The resulting soluble form can interfere with the interaction between HA and membrane-bound CD44. Soluble CD44 can abolish the cell proliferation-promoting effect of HA on melanoma cell lines, suggesting that a better understanding of the shedding process might identify ways of blocking tumor cell proliferation. ADAM10, ADAM17, and MMP14 have previously been implicated in the shedding of CD44 from various tumor cells. Using immunohistochemistry we demonstrate that ADAM10 and ADAM17 but not MMP14 are significantly expressed on melanoma cells in histological sections. In human melanoma cell lines expression of these proteases could be blocked by transfection with appropriate siRNAs. However, only blocking of ADAM10 expression led to decreased shedding of CD44. In parallel, cell proliferation was promoted. Confocal microscopy demonstrated that ADAM10 and CD44 colocalize on the cell surface. We conclude that ADAM10 is the predominant protease involved in the constitutive shedding of endogenous CD44 from melanoma cells, and that enhancement of ADAM10 activity could be an approach to decrease the proliferation of melanoma cells.

Anticancer Chemotherapy Inhibits MHC Class I–Related Chain A Ectodomain Shedding by Downregulating ADAM10 Expression in Hepatocellular Carcinoma

“…Thus, ADAM10, not ADAM17, plays an essential role in the shedding of MICA in human HCC cells. Anderegg and colleagues (23) reported that only ADAM10, not ADAM17, contributed to shedding of CD44 molecules in human melanoma cells although both ADAM10 and ADAM17 proteases were significantly expressed in human melanoma tissues, suggesting that ADAM10 and ADAM17 do not always work in a similar manner. A recent report showed that ADAM10, but not ADAM17, could directly bind to calmodulin (24), which may involve the difference of MICA cleavage between ADAM10 and ADAM17 proteases.…”

ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells

“…Pan et al (32) found that in the pituitary adenoma cell line, AtT-20, ADAM10 facilitated cell migration through modulation of CD44 and L1 cleavage. In another study, Anderegg et al (33) showed that ADAM10 is the predominant protease involved in the constitutive shedding of endogenous CD44 from melanoma cells. Multiple cell signaling pathways are responsible for cellular proliferation and migration (34).…”

Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated Cancer Cell Migration

“…4). It has been demonstrated that cleavage of CD44 by MMP-14 is a prerequisite for MMP-14-enhanced cell migration (9,33,42,43), although MMP-14 is reported to be unnecessary for CD44-shedding in melanoma cells (44). Using a functional assay, we observed that coexpression of MMP-14 but not catalytic inactive MMP-14 mutant (E 240 3 A) in COS-1 cells significantly reduced cell adhesion ability to hyaluronic acid (a CD44 ligand)-coated culture plates (supplemental Fig.…”