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Mol. Cells

Published online September 13, 2023

© The Korean Society for Molecular and Cellular Biology

The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1

Min-Kyu Kim1,6, Sang-Hyun Han1,6, Tae-Geun Park1, Soo-Hyun Song1, Ja-Youl Lee1, You-Soub Lee1, Seo-Yeong Yoo1, Xin-Zi Chi1, Eung-Gook Kim2, Ju-Won Jang3, Dae Sik Lim4, Andre J. van Wijnen5, Jung-Won Lee1,* , and Suk-Chul Bae1,*

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1Department of Biochemistry, College of Medicine and Institute for Tumour Research, Chungbuk National University, Cheongju 28644, Korea, 2Department of Biochemistry, College of Medicine and Medical Research Center, Chungbuk National University, Cheongju 28644, Korea, 3Department of Biomedical Science, Cheongju University, Cheongju 28503, Korea, 4Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea, 5Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA, 6These authors contributed equally to this work.

Correspondence to : scbae@chungbuk.ac.kr(SCB); jeongwon@chungbuk.ac.kr(JWL)

Received: May 25, 2023; Revised: July 10, 2023; Accepted: July 25, 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

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The Hippo kinase cascade functions as a central hub that relays input from the “outside world” of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor β (TGFβ)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFβ-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFβ signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFβ-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFβ signals and the Hippo pathway (TGFβ→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.

Keywords LATS1/2, restriction point, RUNX3, TAK1, TGFβ, YAP1

Article

On-line First

Mol. Cells

Published online September 13, 2023

Copyright © The Korean Society for Molecular and Cellular Biology.

The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1

Min-Kyu Kim1,6, Sang-Hyun Han1,6, Tae-Geun Park1, Soo-Hyun Song1, Ja-Youl Lee1, You-Soub Lee1, Seo-Yeong Yoo1, Xin-Zi Chi1, Eung-Gook Kim2, Ju-Won Jang3, Dae Sik Lim4, Andre J. van Wijnen5, Jung-Won Lee1,* , and Suk-Chul Bae1,*

1Department of Biochemistry, College of Medicine and Institute for Tumour Research, Chungbuk National University, Cheongju 28644, Korea, 2Department of Biochemistry, College of Medicine and Medical Research Center, Chungbuk National University, Cheongju 28644, Korea, 3Department of Biomedical Science, Cheongju University, Cheongju 28503, Korea, 4Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea, 5Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA, 6These authors contributed equally to this work.

Correspondence to:scbae@chungbuk.ac.kr(SCB); jeongwon@chungbuk.ac.kr(JWL)

Received: May 25, 2023; Revised: July 10, 2023; Accepted: July 25, 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

The Hippo kinase cascade functions as a central hub that relays input from the “outside world” of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor β (TGFβ)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFβ-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFβ signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFβ-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFβ signals and the Hippo pathway (TGFβ→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.

Keywords: LATS1/2, restriction point, RUNX3, TAK1, TGFβ, YAP1

Mol. Cells
Sep 30, 2023 Vol.46 No.9, pp. 527~572
COVER PICTURE
Chronic obstructive pulmonary disease (COPD) is marked by airspace enlargement (emphysema) and small airway fibrosis, leading to airflow obstruction and eventual respiratory failure. Shown is a microphotograph of hematoxylin and eosin (H&E)-stained histological sections of the enlarged alveoli as an indicator of emphysema. Piao et al. (pp. 558-572) demonstrate that recombinant human hyaluronan and proteoglycan link protein 1 (rhHAPLN1) significantly reduces the extended airspaces of the emphysematous alveoli by increasing the levels of TGF-β receptor I and SIRT1/6, as a previously unrecognized mechanism in human alveolar epithelial cells, and consequently mitigates COPD.
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