%0 Journal Article %A Pranetha Baskaran %A Simeon R. Mihaylov %A Elin Vinsland %A Kriti Shah %A Lucy Granat %A Sila K. Ultanir %A Andrew R. Tee %A Jernej Murn %A Joseph M. Bateman %T Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis %D 2022 %R 10.1101/2022.04.08.487575 %J bioRxiv %P 2022.04.08.487575 %X 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 StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2022/05/25/2022.04.08.487575.full.pdf