The CD44s splice isoform is a central mediator for invadopodia activity. Author Pu Zhao, Yilin Xu, Yong Wei, Qiong Qiu, Teng-Leong Chew, Yibin Kang, Chonghui Cheng Publication Year 2016 Type Journal Article Abstract The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh)RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis. Keywords Animals, Mice, Humans, Phosphorylation, Female, Cell Line, Tumor, NIH 3T3 Cells, RNA Interference, RNA, Small Interfering, Breast Neoplasms, Cortactin, Hyaluronan Receptors, Lung Neoplasms, MCF-7 Cells, Matrix Metalloproteinase 14, Mice, Nude, Neoplasm Invasiveness, Neoplasm Transplantation, Podosomes, Protein Isoforms, Transplantation, Heterologous Journal J Cell Sci Volume 129 Issue 7 Pages 1355-65 Date Published 2016 Apr 01 ISSN Number 1477-9137 DOI 10.1242/jcs.171959 Alternate Journal J Cell Sci PMCID PMC6518308 PMID 26869223 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML