2. Academic Validation
  3. Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth

Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth

  • Cancer Res. 2021 Mar 15;81(6):1472-1485. doi: 10.1158/0008-5472.CAN-20-2383.
Shinji Iizuka  # 1 2,  Manuela Quintavalle  # 1,  Jose C Navarro 2,  Kyle P Gribbin 2,  Robert J Ardecky 1,  Matthew M Abelman 1,  Chen-Ting Ma 1,  Eduard Sergienko 1,  Fu-Yue Zeng 1,  Ian Pass 1,  George V Thomas 3,  Shannon K McWeeney 3 4 5,  Christian A Hassig 1,  Anthony B Pinkerton 1,  Sara A Courtneidge 6 2 3 7
Affiliations

Affiliations

  • 1 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
  • 2 Department of Cell Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon.
  • 3 Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
  • 4 Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, Oregon.
  • 5 Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, Oregon.
  • 6 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. courtneidge@ohsu.edu.
  • 7 Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon.
  • # Contributed equally.
PMID: 33414172 DOI: 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 affects invadopodia formation. Among the top hits selected for further analysis was TAO3, an 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 three-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. SIGNIFICANCE: An unbiased screening approach identifies TAO3 as a regulator of invadopodia formation and function, supporting clinical development of this class of target.

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