DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity

DYRK1A, a ubiquitously expressed kinase , is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A , is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.

Authors

Institutions

Publication Details

Journal
eLife
Published
2024-10-22
DOI
https://doi.org/10.7554/elife.88318.3
Citations
3
Primary Topic
Down syndrome and intellectual disability research
Type
article
Field-Weighted Citation Impact
1.63

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity

Nandan Jayaram, Sonal Nagarkar-Jaiswal, Tingting Xiao, Michael P. Washburn et al.
3 citations
eLife
Down syndrome and intellectual disability research
1.63
article

DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity

Nandan Jayaram, Sonal Nagarkar-Jaiswal, Tingting Xiao, Michael P. Washburn, Deepa Balasubramanian, Chao Peng, Ruyu He, Pinhua Wang, Sayantan Datta, Manish Jaiswal, Sunayana Sarkar, Laurence Florens, Man Mohan, Ying Zhang, Zhe Zhang, Ping Wu, Menghuan Zhang, Fenhua Kong
article en
3 citations

Abstract

DYRK1A, a ubiquitously expressed kinase , is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A , is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.

eLifeVol. 12
Kunming University of Science and Technology (CN), Stowers Institute for Medical Research (US), Tata Institute of Fundamental Research (IN), Shanghai Jiao Tong University (CN), Centre for Cellular and Molecular Biology (IN), The University of Kansas Cancer Center (US), Protein Express (United States) (US), University of Kansas Medical Center (US), Academy of Scientific and Innovative Research (IN)
Stowers Institute for Medical Research, Department of Biotechnology, Ministry of Science and Technology, India, Department of Science and Technology, Ministry of Science and Technology, India, Department of Atomic Energy, Government of India, National Natural Science Foundation of China, The Wellcome Trust DBT India Alliance
Openalex Percentile: Top 15%
Down syndrome and intellectual disability research
1.63
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.