RT Journal Article
SR Electronic
T1 The serine-threonine kinase TAO3 promotes cancer invasion and tumor growth by facilitating trafficking of endosomes containing the invadopodia scaffold TKS5α
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.27.968305
DO 10.1101/2020.02.27.968305
A1 Shinji Iizuka
A1 Manuela Quintavalle
A1 Jose Ceja Navarro
A1 Kyle P. Gribbin
A1 Robert J. Ardecky
A1 Matthew Abelman
A1 Chen-Ting Ma
A1 Eduard Sergienko
A1 Fu-Yue Zeng
A1 Ian Pass
A1 George Thomas
A1 Shannon McWeeney
A1 Christian A. Hassig
A1 Anthony B Pinkerton
A1 Sara A Courtneidge
YR 2020
UL http://biorxiv.org/content/early/2020/02/28/2020.02.27.968305.abstract
AB Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. We used our high-content screening assay to identify kinases impacting invadopodia formation. Among the top hits we selected TAO3, a STE20-like kinase of the GCK subfamily, for further analysis. TAO3 was over-expressed 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. We developed potent catalytic inhibitors of TAO3 that inhibited invadopodia formation and function, and tumor cell extravasation and growth. Using these inhibitors, we determined that TAO3 activity was 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 Targeting tumor invasive behavior represents an understudied opportunity. We used an unbiased screening approach to identify kinases required for invadopodia formation and function. We validated TAO3, both genetically and with a novel inhibitor, and determined TAO3 function. Our data support clinical development of this class of target.