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KMID : 0578320230460100592
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Molecules and Cells
2023 Volume.46 No. 10 p.592 ~ p.610
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The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1
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Kim Min-Kyu
Han Sang-Hyun
Park Tae-Geun
Song Soo-Hyun
Lee Ja-Youl
Lee You-Soub
Yoo Seo-Yeong
Xin-Zi Chi
Kim Eung-Gook
Jang Ju-Won
Lim Dae-Sik
Andre J. van Wijnen
Lee Jung-Won
Bae Suk-Chul
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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.
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KEYWORD
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LATS1/2, restriction point, RUNX3, TAK1, TGFβ, YAP1
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