Novel Function for a Matrix Metalloprotease

Abstract

As the family name clearly implies, matrix metalloproteases (MMPs) are localized to the extracellular matrix, where they function as proteases, modulating cell signaling by cleaving proteins such as growth factors or growth factor receptors. In the past few years, MMPs in some cell types have also been observed to function in the nucleus. Eguchi et al. implicate MMPs in a nuclear function that does not require its proteolytic activity, however. This alternative function was first suggested when the authors identified MMP3 in a screen for transcriptional regulators of the gene encoding connective tissue growth factor (CTGF), an insulin-like growth factor implicated in diverse physiological and morphogenetic processes, including arthritis, angiogenesis, and wound healing. MMP3 was detected in the nuclei of mouse chondrocytes both in vitro and in vivo, and in vitro knockdown of MMP3 by RNA interference suggested that MMP3 activated CTGF transcription. MMP3’s interaction with the CTGF promoter was direct and sequence-specific, as assayed by a luciferase reporter system and band-shift experiments. Furthermore, the catalytic domain of MMP3 was not required for its DNA-binding or transcriptional activator functions. Finally, binding to the CTGF enhancer was limited to MMP3; overexpression or inhibition of other MMPs did not affect CTGF expression. The results presented in this study suggest an unconventional role for MMPs in the regulation of gene expression. T. Eguchi, S. Kubota, K. Kawata, Y. Mukudai, J. Uehara, T. Ohgawara, S. Ibaragi, A. Sasaki, T. Kuboki, M. Takigawa, Novel transcription factor-like function of human matrix metalloproteinase 3 regulating the CTGF/CCN2 gene. Mol. Cell. Biol. 28 , 2391-2413 (2008). [Abstract] [Full Text]