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J Cell Sci. 2016 Jul 15;129(14):2804-16. doi: 10.1242/jcs.188045. Epub 2016 Jun 8.

Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells.

Author information

1
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75390, USA nawal.bendris@utsouthwestern.edu sandra.schmid@utsouthwestern.edu.
2
Department of Molecular Medicine, Veterinary Medical Center, Cornell University, Ithaca, NY14853, USA.
3
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75390, USA.
4
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX77030, USA.
5
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX77030, USA Department of Pathology, Xuzhou Medical College, Province of Jiangsu, China.
6
Simmons Cancer Center, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX390, USA.

Abstract

The ability of cancer cells to degrade the extracellular matrix and invade interstitial tissues contributes to their metastatic potential. We recently showed that overexpression of sorting nexin 9 (SNX9) leads to increased cell invasion and metastasis in animal models, which correlates with increased SNX9 protein expression in metastases from human mammary cancers. Here, we report that SNX9 expression is reduced relative to neighboring normal tissues in primary breast tumors, and progressively reduced in more aggressive stages of non-small-cell lung cancers. We show that SNX9 is localized at invadopodia where it directly binds the invadopodia marker TKS5 and negatively regulates invadopodia formation and function. SNX9 depletion increases invadopodia number and the local recruitment of MT1-MMP by decreasing its internalization. Together, these effects result in increased localized matrix degradation. We further identify SNX9 as a Src kinase substrate and show that this phosphorylation is important for SNX9 activity in regulating cell invasion, but is dispensable for its function in regulating invadopodia. The diversified changes associated with SNX9 expression in cancer highlight its importance as a central regulator of cancer cell behavior.

KEYWORDS:

Extracellular matrix; Invadopodia; MT1-MMP; SNX9; Src kinase; TKS5

PMID:
27278018
PMCID:
PMC4958298
DOI:
10.1242/jcs.188045
[Indexed for MEDLINE]
Free PMC Article

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