Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells.
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.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75390, USA nawal.bendris@utsouthwestern.edu sandra.schmid@utsouthwestern.edu.
Nawal
0000-0002-6253-9752
N
Bendris
Department of Molecular Medicine, Veterinary Medical Center, Cornell University, Ithaca, NY14853, USA.
Carrie J S
CJ
Stearns
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75390, USA.
Carlos R
0000-0002-8193-6964
CR
Reis
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX77030, USA.
Jaime
0000-0002-0885-2377
J
Rodriguez-Canales
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.
Hui
H
Liu
Simmons Cancer Center, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX390, USA.
Agnieszka W
0000-0001-9467-4169
AW
Witkiewicz
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX75390, USA nawal.bendris@utsouthwestern.edu sandra.schmid@utsouthwestern.edu.
Sandra L
0000-0002-1690-7024
SL
Schmid
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004705:Endocytosis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D010766:Phosphorylation; D000069261:Podosomes / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D058305:Sorting Nexins / Q000378:metabolism*; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D014408:Biomarkers, Tumor; C478582:SH3PXD2A protein, human; C400533:SNX9 protein, human; D058305:Sorting Nexins; D019061:src-Family Kinases; D053511:Matrix Metalloproteinase 14
Extracellular matrix; Invadopodia; MT1-MMP; SNX9; Src kinase; TKS5