Abstract
The cell surface receptor tyrosine kinase (RTK) exists in a dynamic state, however, it remains unknown how single membrane-spanning RTK proteins are retained in the plasma membrane before their activation. This study was undertaken to investigate how RTK proteins are anchored in the plasma membrane before they bind with their respective extracellular ligands for activation through protein–protein interaction, co-localization, and functional phenotype studies. Here we show that unconventional myosin-I MYO1D functions to hold members of the EGFR family (except ErbB3) at the plasma membrane. MYO1D binds only with unphosphorylated EGFRs and anchors them to underlying actin cytoskeleton at the plasma membrane. The C-terminal end region of the MYO1D tail domain containing a β-meander motif is critical for direct binding with kinase domain of the EGFR family, and expression of the tail domain alone suppresses the oncogenic action of full-length MYO1D. Overexpressed MYO1D increases colorectal and breast cancer cell motility and viability through upregulating EGFR level, and thereby promotes colorectal tumor progression in a syngeneic mouse model. MYO1D is upregulated in human colorectal cancer tissues from advanced stages. Collectively, molecular motor MYO1D plays a distinct role in the dynamic regulation of EGFR family levels by holding them at the plasma membrane before their activation. Overexpressed MYO1D contributes to colorectal carcinogenesis possibly as a novel oncogene and thus may serve as an additional target for suppression of RTK signaling in cancer treatment.
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Change history
21 April 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41388-021-01675-y
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Acknowledgements
This work was supported by the National Research Foundation of Korea grant (NRF-2018R1A5A2024181, NRF-2017R1A2B2002040) funded by the Korea government (MSIP). KYS (NRF-2017R1A6A3A11031332) and JAB (NRF-2015R1C1A2A01052689) were partly supported by the by the National Research Foundation of Korea grant.
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The original online version of this article was revised: Following the publication of this article, the authors noted three invasion images in Figure 7 were repeated; the two images in Fig 7a (EV, WT) and one image in Fig 7b (TH) were repeated in Fig 7c (EV, WT, TH).
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Ko, YS., Bae, J.A., Kim, K.Y. et al. MYO1D binds with kinase domain of the EGFR family to anchor them to plasma membrane before their activation and contributes carcinogenesis. Oncogene 38, 7416–7432 (2019). https://doi.org/10.1038/s41388-019-0954-8
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DOI: https://doi.org/10.1038/s41388-019-0954-8
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