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Article

TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression

by
Svetlana A. Mikheeva
1,2,3,
Nathan D. Camp
3,4,5,
Lei Huang
6,
Antrix Jain
7,
Sung Yun Jung
7,
Naze G. Avci
1,
Mari Tokita
8,
Alejandro Wolf-Yadlin
9,
Jing Zhang
10,
Stephen J. Tapscott
11,
Robert C. Rostomily
1,2,3,* and
Andrei M. Mikheev
1,2,3,*
1
Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA
2
Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA
3
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
4
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
5
Seattle Children’s Research Institute, Seattle, WA 98101, USA
6
Department of Systems Medicine & Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA
7
Baylor College of Medicine, Houston, TX 77030, USA
8
Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA
9
Seattle Genetics, Bothell, WA 98021, USA
10
Division of Neuropathology, Department of Pathology, University of Washington, Seattle, WA 98195, USA
11
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
 
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*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(9), 1392; https://doi.org/10.3390/cancers11091392
Submission received: 27 July 2019 / Revised: 4 September 2019 / Accepted: 15 September 2019 / Published: 18 September 2019
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Abstract

Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers.
Keywords: TWIST1; dimerization; invasion; glioblastoma; periostin TWIST1; dimerization; invasion; glioblastoma; periostin

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MDPI and ACS Style

Mikheeva, S.A.; Camp, N.D.; Huang, L.; Jain, A.; Jung, S.Y.; Avci, N.G.; Tokita, M.; Wolf-Yadlin, A.; Zhang, J.; Tapscott, S.J.; et al. TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression. Cancers 2019, 11, 1392. https://doi.org/10.3390/cancers11091392

AMA Style

Mikheeva SA, Camp ND, Huang L, Jain A, Jung SY, Avci NG, Tokita M, Wolf-Yadlin A, Zhang J, Tapscott SJ, et al. TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression. Cancers. 2019; 11(9):1392. https://doi.org/10.3390/cancers11091392

Chicago/Turabian Style

Mikheeva, Svetlana A., Nathan D. Camp, Lei Huang, Antrix Jain, Sung Yun Jung, Naze G. Avci, Mari Tokita, Alejandro Wolf-Yadlin, Jing Zhang, Stephen J. Tapscott, and et al. 2019. "TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression" Cancers 11, no. 9: 1392. https://doi.org/10.3390/cancers11091392

APA Style

Mikheeva, S. A., Camp, N. D., Huang, L., Jain, A., Jung, S. Y., Avci, N. G., Tokita, M., Wolf-Yadlin, A., Zhang, J., Tapscott, S. J., Rostomily, R. C., & Mikheev, A. M. (2019). TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression. Cancers, 11(9), 1392. https://doi.org/10.3390/cancers11091392

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