ADAM10 is the constitutive functional sheddase of CD44 in human melanoma cells.
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.
Anderegg
Ulf
U
Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany. Ulf.Anderegg@medizin.uni-leipzig.de
Eichenberg
Thea
T
Parthaune
Tanja
T
Haiduk
Christian
C
Saalbach
Anja
A
Milkova
Linda
L
Ludwig
Andreas
A
Grosche
Jens
J
Averbeck
Marco
M
Gebhardt
Carl
C
Voelcker
Verena
V
Sleeman
Jonathan P
JP
Simon
Jan C
JC
D051722:ADAM Proteins / Q000096:biosynthesis* / Q000502:physiology*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D007150:Immunohistochemistry / Q000379:methods; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis; D008545:Melanoma / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000502:physiology*; D018613:Microscopy, Confocal; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism
D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D053511:Matrix Metalloproteinase 14; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human