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DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity

Authors :
Pinhua Wang
Sunayana Sarkar
Menghuan Zhang
Tingting Xiao
Fenhua Kong
Zhe Zhang
Deepa Balasubramanian
Nandan Jayaram
Sayantan Datta
Ruyu He
Ping Wu
Peng Chao
Ying Zhang
Michael Washburn
Laurence A Florens
Sonal Nagarkar-Jaiswal
Manish Jaiswal
Man Mohan
Source :
eLife, Vol 12 (2024)
Publication Year :
2024
Publisher :
eLife Sciences Publications Ltd, 2024.

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.

Details

Language :
English
ISSN :
2050084X
Volume :
12
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.4350b6428f4542ff8d1561e278254bd9
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.88318