Abstract
To search for the signaling pathway critical for tumor invasion, we examined the effects of dominant negative ras (S17N ras) expression on the activation of matrix metalloproteinase-2 (MMP-2) in src-transformed 3Y1, SR3Y1, under the control of conditionally inducible promoter. In SR3Y1 clones transfected with S17N ras, augmented secretion and proteolytic activation of MMP-2 were dramatically suppressed by S17N Ras expression, while tyrosine phosphorylation of cellular proteins was not suppressed. We found that invasiveness of SR3Y1 cells assayed by the modified Boyden Chamber method was strongly suppressed by S17N Ras expression. In contrast, cell morphology reverted partially and glucose uptake remained unchanged by S17N Ras expression. In addition, treatment of SR3Y1 with manumycin A, a potent inhibitor of Ras farnesyltransferase, strongly suppressed both augmented secretion and proteolytic activation of MMP-2. Contrary, treatment of SR3Y1 with wortmannin or TPA showed no clear effect on MMP-2 activation. Thus, these results strongly suggest that Ras-signaling, but neither P13 kinase- nor protein kinase C-signalings, plays a critical role in activation of MMP-2 and, subsequently, in the invasiveness of src-transformed cells.
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Acknowledgements
We are greatly indebted to Hideosaburo Hanafusa for his continuous encouragement and support. We thank Aninya Dutta for his helpful discussion, Lary A Feig for his gift of S17N ras, Joan S Brugge for her gift of monoclonal antibody 327, Fumiko Yamauchi for her excellent technical assistance. This work was supported by a Grant-in-Aid for scientific research on priority areas and for COE Research from the Ministry of Education, Science and Culture of Japan, a Grant under the Monbusho International Scientific Research Program, Sankyo Foundation of Life Science and Naito Foundation.
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Thant, A., Sein, T., Liu, E. et al. Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1. Oncogene 18, 6555–6563 (1999). https://doi.org/10.1038/sj.onc.1203049
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DOI: https://doi.org/10.1038/sj.onc.1203049
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