Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth
- 7 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (6), 1472-1485
- https://doi.org/10.1158/0008-5472.can-20-2383
Abstract
Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity impacts invadopodia formation. Among the top hits selected for further analysis was TAO3, a STE20-like kinase of the GCK subfamily. TAO3 was overexpressed in many human cancers and regulated invadopodia formation in melanoma, breast, and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in 3-dimensional matrices and in vivo. A novel, potent catalytic inhibitor of TAO3 was developed that inhibited invadopodia formation and function as well as tumor cell extravasation and growth. Treatment with this inhibitor demonstrated that TAO3 activity is required for endosomal trafficking of TKS5α, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein subunit protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation. Thus, TAO3 is a new therapeutic target with a distinct mechanism of action.Other Versions
Funding Information
- NIH (P30 CA069533, R01 CA154002)
- NCI
- NIH
- Knight Cancer Institute (R01 CA169172)
This publication has 61 references indexed in Scilit:
- Functional genomics identifies therapeutic targets for MYC-driven cancerProceedings of the National Academy of Sciences of the United States of America, 2012
- Rapid and Reproducible Single-Stage Phosphopeptide Enrichment of Complex Peptide Mixtures: Application to General and Phosphotyrosine-Specific Phosphoproteomics ExperimentsAnalytical Chemistry, 2011
- A Cell-Based High-Content Screening Assay Reveals Activators and Inhibitors of Cancer Cell InvasionScience Signaling, 2011
- The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and functionNature Reviews Molecular Cell Biology, 2011
- Recruitment of dynein to late endosomes and lysosomes through light intermediate chainsMolecular Biology of the Cell, 2011
- Actin, microtubules, and vimentin intermediate filaments cooperate for elongation of invadopodiaThe Journal of cell biology, 2010
- The (un)targeted cancer kinomeNature Chemical Biology, 2010
- A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivoEuropean Journal of Cell Biology, 2008
- Cortactin in tumor invasivenessCancer Letters, 2008
- Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cellsThe EMBO Journal, 2000