Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit α4
Open accessAbstract
Opitz syndrome (OS) is a human genetic disease characterized by deformities such as cleft palate that are attributable to defects in embryonic development at the midline. Gene mapping has identified OS mutations within a protein called Mid1. Wild-type Mid1 predominantly colocalizes with microtubules, in contrast to mutant versions of Mid1 that appear clustered in the cytosol. Using yeast two-hybrid screening, we found that the alpha4-subunit of protein phosphatases 2A/4/6 binds Mid1. Epitope-tagged alpha4 coimmunoprecipitated endogenous or coexpressed Mid1 from COS7 cells, and this required only the conserved C-terminal region of alpha4. Localization of Mid1 and alpha4 was influenced by one another in transiently transfected cells. Mid1 could recruit alpha4 onto microtubules, and high levels of alpha4 could displace Mid1 into the cytosol. Metabolic (32)P labeling of cells showed that Mid1 is a phosphoprotein, and coexpression of full-length alpha4 decreased Mid1 phosphorylation, indicative of a functional interaction. Association of green fluorescent protein-Mid1 with microtubules in living cells was perturbed by inhibitors of MAP kinase activation. The conclusion is that Mid1 association with microtubules, which seems important for normal midline development, is regulated by dynamic phosphorylation involving MAP kinase and protein phosphatase that is targeted specifically to Mid1 by alpha4. Human birth defects may result from environmental or genetic disruption of this regulatory cycle.
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α4 binds partially folded PP2A/C, stabilizing it in a latent state and preventing its ubiquitination and degradation by MID1.
“It has been shown that partially folded PP2A/C is stabilized for latency by the binding of α4, which in part prevents its ubiquitination and subsequent degradation by Midline 1 (MID1) (Jiang et al., 2013; Liu et al., 2001; Short et al., 2002).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Liu et al., 2001
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- Authors
- Liu, J., Prickett, T. D., Elliott, E., Meroni, G., & Brautigan, D. L.
- Affiliations
- Telethon Institute Of Genetics And Medicine (IT)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-05-22
- Volume
- 98
- Issue
- 12
- Pages
- 6650-6655
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC34408
- OpenAlex
- W2089156548
- Cited by
- 100
- References
- 24
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 5 · 2014: 6 · 2013: 5 · 2012: 6
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- Funders
- W. M. Keck Foundation
- March of Dimes Foundation
- U.S. Public Health Service
- National Cancer Institute (CA 77584, R01CA077584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Opitz syndrome, MID1, protein phosphatase 2A, protein phosphorylation, microtubule association, mitogen-activated protein kinase, cleft palate, protein-protein interaction
- MeSH terms
- Animals, Microtubule Proteins, Microtubules, Mutation, Nuclear Proteins, Phosphoprotein Phosphatases, Phosphorylation, Transcription Factors, COS Cells, Protein Subunits, Ubiquitin-Protein Ligases, Mice, Protein Phosphatase 2
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