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bioRxiv · 10.1101/2020.07.24.218313

DOCK5 couples CDC42-GSK3beta activation with focal adhesion morphogenesis to reinforce the establishment of polarity and promote YAP/TAZ activation during migration.

Pascual-Vargas, P. P.·Arias-Garcia, M.·Roumeliotis, T. I.·Chaudhary, J. S.·Bakal, C.
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Abstract

YAP and TAZ are transcriptional co-activators that are often constitutively active in triple negative breast cancer (TNBC) cells driving proliferation, invasion, and drug resistance. Through multiplexed quantitative genetic screens for YAP/TAZ localisation and cell shape, we found that the RhoGEF DOCK5 is essential for YAP/TAZ activation in metastatic cells and is required for the maintenance of polarity during migration. DOCK5 regulates cell shape and thus YAP/TAZ through different genetic interactions with CDC42, RAC, and RHOA GTPases. DOCK5 regulates focal adhesion (FA) morphogenesis in RAC-dependent fashions that promote RHOA mediated actomyosin engagement of FA. Using unbiased systems-level quantification of protein levels by mass spectrometry we show that DOCK5 maintains polarity by stabilising protein levels of the CDC42 effector GSK3{beta}. We conclude DOCK5 acts as a coincidence detector to promote leading edge persistence in subcellular locations where there is both RAC and RHOA dependent FA morphogenesis and active CDC42 mediated cell polarisation.

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Pascual-Vargas, P. P., Arias-Garcia, M., Roumeliotis, T. I., Chaudhary, J. S., Bakal, C.. 2020-07-24. DOCK5 couples CDC42-GSK3beta activation with focal adhesion morphogenesis to reinforce the establishment of polarity and promote YAP/TAZ activation during migration.. https://doi.org/10.1101/2020.07.24.218313

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