Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

Ying Wei Li, Jin Guo, He Shen, Jun Li, Nuo Yang, Costa Frangou, Kayla E. Wilson, Yinglong Zhang, Ashley L. Mussell, Marius Sudol, Amjad Farooq, Jun Qu, Jianmin Zhang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP1, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. The Hippo tumor suppressor pathway has been suggested to inhibit the YAP1 function through serine phosphorylation-induced cytoplasmic retention and degradation. Here we report that the tyrosine188 (Y188) site of YAP1 isoform with 2 WW domains (known as YAP1-2) plays an important role in YAP1-induced cellular transformation. IP-Mass Spectrometry analysis of YAP1 identified the phosphorylation of Y188 but not other tyrosine residues. In contrast to the aberrant 3D acinus formation observed in YAP1-WT transduced cells, overexpression of YAP1-Y188F (non-phosphorylated mimic) displayed normal 3D structures. In addition, knockdown of the endogenous YAP1 in MDA-MB231 breast cancer cells inhibited cell proliferation and migration, which were then successfully rescued by the exogenous YAP1-WT and YAP1-Y188E but not Y188F. Mechanistically, we also demonstrated that YAP1-Y188F had a higher affinity to the upstream negative regulator PTPN14 and was extensively localized in the cytoplasm. Since the Y188 is located in the conserved aromatic core of the WW domain of YAP1, our finding has a wide implication for WW domain signaling in general, where Y phosphorylation may act as a common positive regulator of the complex formation via WW domains. In summary, our results indicate that tyrosine 188 plays an important role in the YAP1-induced cellular transformation and its phosphorylation may intriguingly serve as a positive indicator of YAP1 activation.

Original languageEnglish (US)
Pages (from-to)2497-2505
Number of pages9
JournalCell Cycle
Volume15
Issue number18
DOIs
StatePublished - Sep 16 2016

Fingerprint

Phosphorylation
Tyrosine
Cell Proliferation
Epithelial-Mesenchymal Transition
Serine
Cell Movement
Mass Spectrometry
Neoplasms
Protein Isoforms
Carcinogenesis
Cytoplasm
Breast Neoplasms
Survival

Keywords

  • cellular transformation
  • Hippo pathway
  • tyrosine phosphorylation
  • YAP1

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation. / Li, Ying Wei; Guo, Jin; Shen, He; Li, Jun; Yang, Nuo; Frangou, Costa; Wilson, Kayla E.; Zhang, Yinglong; Mussell, Ashley L.; Sudol, Marius; Farooq, Amjad; Qu, Jun; Zhang, Jianmin.

In: Cell Cycle, Vol. 15, No. 18, 16.09.2016, p. 2497-2505.

Research output: Contribution to journalArticle

Li, YW, Guo, J, Shen, H, Li, J, Yang, N, Frangou, C, Wilson, KE, Zhang, Y, Mussell, AL, Sudol, M, Farooq, A, Qu, J & Zhang, J 2016, 'Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation', Cell Cycle, vol. 15, no. 18, pp. 2497-2505. https://doi.org/10.1080/15384101.2016.1207836
Li, Ying Wei ; Guo, Jin ; Shen, He ; Li, Jun ; Yang, Nuo ; Frangou, Costa ; Wilson, Kayla E. ; Zhang, Yinglong ; Mussell, Ashley L. ; Sudol, Marius ; Farooq, Amjad ; Qu, Jun ; Zhang, Jianmin. / Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation. In: Cell Cycle. 2016 ; Vol. 15, No. 18. pp. 2497-2505.
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T1 - Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

AU - Li, Ying Wei

AU - Guo, Jin

AU - Shen, He

AU - Li, Jun

AU - Yang, Nuo

AU - Frangou, Costa

AU - Wilson, Kayla E.

AU - Zhang, Yinglong

AU - Mussell, Ashley L.

AU - Sudol, Marius

AU - Farooq, Amjad

AU - Qu, Jun

AU - Zhang, Jianmin

PY - 2016/9/16

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N2 - The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP1, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. The Hippo tumor suppressor pathway has been suggested to inhibit the YAP1 function through serine phosphorylation-induced cytoplasmic retention and degradation. Here we report that the tyrosine188 (Y188) site of YAP1 isoform with 2 WW domains (known as YAP1-2) plays an important role in YAP1-induced cellular transformation. IP-Mass Spectrometry analysis of YAP1 identified the phosphorylation of Y188 but not other tyrosine residues. In contrast to the aberrant 3D acinus formation observed in YAP1-WT transduced cells, overexpression of YAP1-Y188F (non-phosphorylated mimic) displayed normal 3D structures. In addition, knockdown of the endogenous YAP1 in MDA-MB231 breast cancer cells inhibited cell proliferation and migration, which were then successfully rescued by the exogenous YAP1-WT and YAP1-Y188E but not Y188F. Mechanistically, we also demonstrated that YAP1-Y188F had a higher affinity to the upstream negative regulator PTPN14 and was extensively localized in the cytoplasm. Since the Y188 is located in the conserved aromatic core of the WW domain of YAP1, our finding has a wide implication for WW domain signaling in general, where Y phosphorylation may act as a common positive regulator of the complex formation via WW domains. In summary, our results indicate that tyrosine 188 plays an important role in the YAP1-induced cellular transformation and its phosphorylation may intriguingly serve as a positive indicator of YAP1 activation.

AB - The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP1, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. The Hippo tumor suppressor pathway has been suggested to inhibit the YAP1 function through serine phosphorylation-induced cytoplasmic retention and degradation. Here we report that the tyrosine188 (Y188) site of YAP1 isoform with 2 WW domains (known as YAP1-2) plays an important role in YAP1-induced cellular transformation. IP-Mass Spectrometry analysis of YAP1 identified the phosphorylation of Y188 but not other tyrosine residues. In contrast to the aberrant 3D acinus formation observed in YAP1-WT transduced cells, overexpression of YAP1-Y188F (non-phosphorylated mimic) displayed normal 3D structures. In addition, knockdown of the endogenous YAP1 in MDA-MB231 breast cancer cells inhibited cell proliferation and migration, which were then successfully rescued by the exogenous YAP1-WT and YAP1-Y188E but not Y188F. Mechanistically, we also demonstrated that YAP1-Y188F had a higher affinity to the upstream negative regulator PTPN14 and was extensively localized in the cytoplasm. Since the Y188 is located in the conserved aromatic core of the WW domain of YAP1, our finding has a wide implication for WW domain signaling in general, where Y phosphorylation may act as a common positive regulator of the complex formation via WW domains. In summary, our results indicate that tyrosine 188 plays an important role in the YAP1-induced cellular transformation and its phosphorylation may intriguingly serve as a positive indicator of YAP1 activation.

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