Mitotic CDK1 and 4E-BP1 II: A single phosphomimetic mutation in 4E-BP1 induces glucose intolerance in mice

• DOI: 10.1371/journal.pone.0282914
• Publication Date: 2023-03-10T18:24:01Z
• Authors: Simon Cao; Michael J. Jurczak; Yoko Shuda; Rui Sun; Masahiro Shuda; Yuan Chang; Patrick S. Moore
• Keywords: Male; Science; Q; R; Cell Cycle Proteins; Mechanistic Target of Rapamycin Complex 1; Phosphoproteins; Synapsins; Mice; Glucose; CDC2 Protein Kinase; Glucose Intolerance; Mutation; Medicine; Humans; Animals; Phosphorylation; Research Article; Adaptor Proteins, Signal Transducing

Objective Cyclin-dependent kinase 1 (CDK1)/cyclin B1 phosphorylates many of the same substrates as mTORC1 (a key regulator glucose metabolism), including eukaryotic initiation factor 4E-binding protein (4E-BP1). Only mitotic CDK1 4E-BP1 at residue S82 in mice (S83 humans), addition to common phospho-acceptor sites phosphorylated by both and mTORC1. We examined metabolism having a single aspartate phosphomimetic amino acid knock substitution serine 82 (4E-BP1 S82D ) mimicking constitutive phosphorylation. Methods Knock-in homozygous S82A C57Bl/6N were assessed for tolerance testing (GTT) metabolic cage analysis on regular high-fat chow diets. Gastrocnemius tissues from WT subject Reverse Phase Protein Array analysis. Since bone marrow is one few typically cycling cells that transit mitosis, reciprocal bone-marrow transplants performed between male mice, followed assessment, determine role actively homeostasis. Results Homozygous knock-in showed intolerance was markedly accentuated with diabetogenic diet (p = 0.004). In contrast, unphosphorylatable alanine had normal tolerance. profiling lean muscle tissues, largely arrested G 0 , did not show expression or signaling changes could account these results. Reciprocal transplantation wild-type littermates revealed trend engraftment diets become hyperglycemic after challenge. Conclusions induces mice. These findings indicate may be regulated phosphorylation independent mTOR point towards an unexpected mitosis diabetic control.