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Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis

Pranetha Baskaran, Simeon R. Mihaylov, Elin Vinsland, Kriti Shah, Lucy Granat, Sila K. Ultanir, Andrew R. Tee, Jernej Murn, View ORCID ProfileJoseph M. Bateman
doi: https://doi.org/10.1101/2022.04.08.487575
Pranetha Baskaran
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RX, UK
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Simeon R. Mihaylov
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RX, UK
2Kinases and Brain Development Lab, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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Elin Vinsland
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RX, UK
3Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
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Kriti Shah
4Department of Biochemistry, University of California, Riverside, 3401 Watkins Drive, Boyce Hall 1415A - MURN, Riverside, CA 92521, USA
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Lucy Granat
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RX, UK
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Sila K. Ultanir
2Kinases and Brain Development Lab, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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Andrew R. Tee
5Cancer and Genetics Building, Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park Way, Cardiff, CF14 4XN, UK
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Jernej Murn
4Department of Biochemistry, University of California, Riverside, 3401 Watkins Drive, Boyce Hall 1415A - MURN, Riverside, CA 92521, USA
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  • For correspondence: murnj@ucr.edu joseph_matthew.bateman@kcl.ac.uk
Joseph M. Bateman
1Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RX, UK
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  • ORCID record for Joseph M. Bateman
  • For correspondence: murnj@ucr.edu joseph_matthew.bateman@kcl.ac.uk
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Abstract

Mechanistic target of rapamycin (mTOR) is a protein kinase that integrates multiple inputs to regulate anabolic cellular processes. mTOR complex I (mTORC1) has key functions in growth control, autophagy and metabolism. Much less is known about the signalling components that act downstream of mTORC1 that regulate cellular morphology, a vital determinant of cellular function. Here we show that the RNA-binding protein Unkempt, a key regulator of cellular morphogenesis, is a novel substrate mTORC1. We find that Unkempt phosphorylation is regulated by nutrient levels and growth factors via mTORC1. Furthermore, Unkempt physically interacts with and is directly phosphorylated by mTORC1 through binding to the regulatory-associated protein of mTOR, Raptor. Phosphorylation of Unkempt, which we find is mTORC1-dependent in cultured mammalian cell lines as well as in primary tissues, occurs largely within the highly serine-rich intrinsically disordered region of Unkempt. Importantly, mutation analysis of this region indicates that phosphorylation inhibits the ability of Unkempt to induce a bipolar morphology. Our findings reveal a novel molecular link between mTORC1 signalling and cellular morphogenesis.

Competing Interest Statement

The authors have declared no competing interest.

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Posted May 25, 2022.
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Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis
Pranetha Baskaran, Simeon R. Mihaylov, Elin Vinsland, Kriti Shah, Lucy Granat, Sila K. Ultanir, Andrew R. Tee, Jernej Murn, Joseph M. Bateman
bioRxiv 2022.04.08.487575; doi: https://doi.org/10.1101/2022.04.08.487575
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Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis
Pranetha Baskaran, Simeon R. Mihaylov, Elin Vinsland, Kriti Shah, Lucy Granat, Sila K. Ultanir, Andrew R. Tee, Jernej Murn, Joseph M. Bateman
bioRxiv 2022.04.08.487575; doi: https://doi.org/10.1101/2022.04.08.487575

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