Serine-threonine kinase TAO3 mediated trafficking of endosomes containing the invadopodia scaffold TKS5-alpha promotes cancer invasion and tumor growth

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, for further analysis. 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, and tumor cell extravasation, and growth. Treatment with these inhibitors demonstrated that TAO3 activity is required for endosomal trafficking of TKS5-alpha, 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Cutaneous Malignant Melanoma 1

SUBMITTER: Phillip Wilmarth  

LAB HEAD: Dr. Sara A. Courtneidge

PROVIDER: PXD023867 | Pride | 2021-01-29

REPOSITORIES: Pride