Pro-Metastatic Matrix Metalloproteinase Expression is Induced by the Invadopodial and Cytoskeletal Regulators Glycine- and Cysteine-Rich Proteins 1 and 2

Abstract

The actin cytoskeleton has multiple functions in cancer cell invasion and metastasis; yet how these functions are coordinated remains unclear. In the cytoplasm, actin is necessary for the formation of specialized membrane protrusions, termed invadopodia, that concentrate and secrete extracellular matrix-degrading enzymes, particularly the matrix metalloproteinases (MMPs), facilitating tumor cell invasion. We recently identified cysteine- and glycine-rich protein 2 (CSRP2) as an actin-crosslinking protein whose activity is required for the assembly and elongation of the invadopodium actin backbone. We report here that this cytoskeletal regulator also translocates to the nucleus in breast cancer cells to induce a complementary pro-metastasis gene expression program. Our data indicate that CSRP2 interacts with the transcription factor serum response factor (SRF) to transcriptionally up-regulate MMP13, a key mediator of tumor cell invasion. Additionally, we found that the closely related CSRP1, previously characterized as an important differentation factor in smooth muscle cells, is similarly critical for the invasive behavior of breast cancer cells. It also exhibits a dual cytoplasmic/nuclear subcellular distribution and upregulates expression of pro-metastatic MMPs, in particular that of MMP14, considered as a master pro-metastatic MMP. Therefore, we propose that CSRP1 and CSRP2 represent a new type of metastasis coordinator, directly enabling both function of invadopodia and expression of the MMPs required for their activity.