ADAM15 suppresses cell motility by driving integrin alpha5beta1 cell surface expression via Erk inactivation.
Human ADAM15 is unique among the A disintegrin and metalloprotease domain (ADAM) family because of the integrin binding motif Arg-Gly-Asp (RGD) within its disintegrin domain. Integrin alpha5beta1 has been reported to bind to ADAM15 in an RGD-dependent manner, but the biological significance of the interaction between ADAM15 and alpha5beta1 is unknown. To characterize the effects of ADAM15 on alpha5beta1-mediated cell adhesion and migration and elucidate the potential mechanism, CHO cells which express endogenous integrin alpha5beta1 were transfected with human ADAM15 cDNA. ADAM15 overexpression led to enhanced cell adhesion and decreased migration on fibronectin, which were suppressed by down-regulation of integrin alpha5. Overexpression of ADAM15 not only increased the cell surface expression of integrin alpha5 but also resulted in a more clustered staining of alpha5 on cell surface, while the beta1 subunit remained unchanged. Unexpectedly, results from immunoprecipitation and immunofluorescence indicated that ADAM15 and alpha5beta1 integrin did not interact directly in CHO cells. We found that ADAM15 expression decreased the phosphorylation of Erk1/2. Consistently, down-regulation of Erk1/2 phosphorylation by MEK inhibitor PD98059 or siRNA against Erk1/2 enhanced the expression of alpha5 on cell surface. By using a B16F10 pulmonary metastasis model, we revealed that overexpression of ADAM15 significantly reduced the number of metastatic nodules on the lung. Taken together, this study reveals for the first time that ADAM15 could drive alpha5 integrin expression on cell surface via down-regulation of phosphorylated Erk1/2. This presents a novel mechanism by which ADAM15 regulates cell-matrix adhesion and migration.
Chen
Qin
Q
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
Meng
Ling-Hua
LH
Zhu
Cai-Hua
CH
Lin
Li-Ping
LP
Lu
He
H
Ding
Jian
J
D051722:ADAM Proteins / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology*; D002465:Cell Movement; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary; D008545:Melanoma / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D014183:Transplantation, Heterologous
D005353:Fibronectins; D039081:Integrin alpha5beta1; D008565:Membrane Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; C098660:ADAM15 protein, human