Non-canonical functions of a mutant TSC2 protein in mitotic division.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Signal Transduction* ; Tumor Suppressor Proteins*/genetics ; Tumor Suppressor Proteins*/metabolism; Humans ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mutant Proteins ; Tuberous Sclerosis Complex 2 Protein/genetics ; Tuberous Sclerosis Complex 2 Protein/metabolism

Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. TSC is caused by mutations in the TSC1 or TSC2 genes, which encode the hamartin/tuberin proteins respectively. These proteins function as a heterodimer that negatively regulates the mechanistic Target of Rapamycin Complex 1 (mTORC1). TSC research has focused on the effects of mTORC1, a critical signaling hub, on regulation of diverse cell processes including metabolism, cell growth, translation, and neurogenesis. However, non-canonical functions of TSC2 are not well studied, and the potential disease-relevant biological mechanisms of mutations affecting these functions are not well understood. We observed aberrant multipolar mitotic division, a novel phenotype, in TSC2 mutant iPSCs. The multipolar phenotype is not meaningfully affected by treatment with the inhibitor rapamycin. We further observed dominant negative activity of the mutant form of TSC2 in producing the multipolar division phenotype. These data expand the knowledge of TSC2 function and pathophysiology which will be highly relevant to future treatments for patients with TSC.
Competing Interests: MS reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta. He has served on Scientific Advisory Boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics and Alkermes. The other authors have no competing interests to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2023 Chalkley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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P50 HD103537 United States HD NICHD NIH HHS; P50 HD105351 United States HD NICHD NIH HHS; R01 NS118580 United States NS NINDS NIH HHS; T32 HD007502 United States HD NICHD NIH HHS

EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
0 (Mutant Proteins)
0 (Tuberous Sclerosis Complex 2 Protein)
0 (Tumor Suppressor Proteins)
0 (TSC2 protein, human)

Date Created: 20231004 Date Completed: 20231010 Latest Revision: 20240315

20250114

PMC10550124

10.1371/journal.pone.0292086

37792789