Alternative Wnt Signaling Activates YAP/TAZ.
The transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here, we discover YAP/TAZ as bona fide downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/β-catenin signaling. Mechanistically, we delineate the "alternative Wnt-YAP/TAZ signaling axis" that consists of Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling, including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/β-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling.
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Hyun Woo
HW
Park
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Cardiology, Veterans Medical Research Foundation, San Diego, CA 92161, USA.
Young Chul
YC
Kim
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Bo
B
Yu
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Toshiro
T
Moroishi
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Jung-Soon
JS
Mo
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Steven W
SW
Plouffe
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Zhipeng
Z
Meng
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Kimberly C
KC
Lin
Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Fa-Xing
FX
Yu
McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53706, USA.
Caroline M
CM
Alexander
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cun-Yu
CY
Wang
Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
Kun-Liang
KL
Guan
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D051157:Frizzled Receptors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors; D060449:Wnt Signaling Pathway; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D051176:beta Catenin