NEDD9/Arf6-dependent endocytic trafficking of matrix metalloproteinase 14: a novel mechanism for blocking mesenchymal cell invasion and metastasis of breast cancer

NEDD9 is an established marker of invasive and metastatic cancers. NEDD9 downregulation has been shown to dramatically reduce cell invasion and metastasis in multiple tumors. The mechanisms by which NEDD9 regulates invasion are largely unknown. In the current study, we have found that NEDD9 is requi...

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Published in:	Oncogene Vol. 34; no. 28; pp. 3662 - 3675
Main Authors:	Loskutov, Y V, Kozyulina, P Y, Kozyreva, V K, Ice, R J, Jones, B C, Roston, T J, Smolkin, M B, Ivanov, A V, Wysolmerski, R B, Pugacheva, E N
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-07-2015 Nature Publishing Group
Subjects:	Adaptor Proteins, Signal Transducing - metabolism ADP-ribosylation factor ADP-Ribosylation Factors - metabolism Animals Antisense therapy Apoptosis Biomarkers Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer metastasis Cell adhesion & migration Cell Biology Cell Line, Tumor Cell Movement Development and progression Endosomes Endosomes - metabolism Enzyme regulation Female Genetic aspects GTPase-activating protein Guanosine triphosphatases Health aspects HEK293 Cells Human Genetics Humans Internal Medicine Invasiveness Matrix Matrix metalloproteinase Matrix Metalloproteinase 14 - metabolism Medicine Medicine & Public Health Mesenchyme Mesoderm - cytology Mesoderm - pathology Metalloproteinase Metastases Metastasis Mice Neoplasm Metastasis Neoplasm Transplantation Oligonucleotides, Antisense - pharmacology Oncology original-article Phosphoproteins - metabolism Properties Proteases Protein transport Protein turnover Proteins Signal Transduction Therapeutic applications Tissue inhibitor of metalloproteinase 2 Tissue Inhibitor of Metalloproteinase-2 - metabolism Tumor cells Tumors Xenografts
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Summary:	NEDD9 is an established marker of invasive and metastatic cancers. NEDD9 downregulation has been shown to dramatically reduce cell invasion and metastasis in multiple tumors. The mechanisms by which NEDD9 regulates invasion are largely unknown. In the current study, we have found that NEDD9 is required for matrix metalloproteinase 14 (MMP14) enzymatic recovery/recycling through the late endosomes to enable disengagement of tissue inhibitor of matrix metalloproteinase 2 (TIMP2) and tumor invasion. Depletion of NEDD9 decreases targeting of the MMP14/TIMP2 complex to late endosomes and increases trafficking of MMP14 from early/sorting endosomes back to the surface in a small GTPase ADP ribosylation factor-6 (Arf6)-dependent manner. NEDD9 directly binds to Arf6-GTPase-activating protein, ARAP3 and Arf6-effector GGA3, thereby facilitating the Arf6 inactivation required for MMP14/TIMP2 targeting to late endosomes. Re-expression of NEDD9 or a decrease in Arf6 activity is sufficient to restore MMP14 activity and the invasive properties of tumor cells. Importantly, NEDD9 inhibition by Vivo-Morpholinos, an antisense therapy, decreases primary tumor growth and metastasis in xenograft models of breast cancer. Collectively, our findings uncover a novel mechanism to control tumor-cell dissemination through NEDD9/Arf6-dependent regulation of MMP14/TIMP2 trafficking, and validate NEDD9 as a clinically relevant therapeutic target to treat metastatic cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2014.297