Regulation of integrin activity by MIA.
MIA (melanoma inhibitory activity) has been identified as a small protein secreted from malignant melanoma cells, which interacts with extracellular matrix proteins including fibronectin. Here, we show that MIA negatively regulates the activity of the mitogen-activated protein kinase pathway in malignant melanoma. Using far Western blotting and co-immunoprecipitation we searched for MIA-binding cell surface proteins. We found that MIA interacts with integrin alpha4beta1 and alpha5beta1, leading to down-regulation of integrin activity and reduction of mitogen-activated protein kinase signaling. These findings also suggest that MIA may play a role in tumor progression and the spread of malignant melanomas via mediating detachment of cells from extracellular matrix molecules by modulating integrin activity. Inhibiting MIA functions in vivo may therefore provide a novel therapeutic strategy for metastatic melanoma disease.
Bauer
Richard
R
University of Regensburg Medical School, Institute of Pathology, D-93053 Regensburg, Germany.
Humphries
Martin
M
Fässler
Reinhard
R
Winklmeier
Andreas
A
Craig
Sue E
SE
Bosserhoff
Anja-Katrin
AK
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; C090059:MIA protein, human; C513263:Mia protein, mouse; D009363:Neoplasm Proteins; D020928:Mitogen-Activated Protein Kinases