TY - JOUR
T1 - Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5a Promotes Cancer Invasion and Tumor Growth
AU - Iizuka, Shinji
AU - Quintavalle, Manuela
AU - Navarro, Jose C.
AU - Gribbin, Kyle P.
AU - Ardecky, Robert J.
AU - Abelman, Matthew M.
AU - Ma, Chen Ting
AU - Sergienko, Eduard
AU - Zeng, Fu Yue
AU - Pass, Ian
AU - Thomas, George V.
AU - McWeeney, Shannon K.
AU - Hassig, Christian A.
AU - Pinkerton, Anthony B.
AU - Courtneidge, Sara A.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research Inc.. All rights reserved.
PY - 2021/3
Y1 - 2021/3
N2 - 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 TKS5a, 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.
AB - 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 TKS5a, 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.
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U2 - 10.1158/0008-5472.CAN-20-2383
DO - 10.1158/0008-5472.CAN-20-2383
M3 - Article
C2 - 33414172
AN - SCOPUS:85103773084
SN - 0008-5472
VL - 81
SP - 1472
EP - 1485
JO - Cancer Research
JF - Cancer Research
IS - 6
ER -