DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity
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
Affiliations
Pinhua Wang
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
Sunayana Sarkar
Tata Institute of Fundamental Research, Hyderabad, India
Menghuan Zhang
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
Tingting Xiao
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
Fenhua Kong
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
Zhe Zhang
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
Deepa Balasubramanian
Tata Institute of Fundamental Research, Hyderabad, India
Nandan Jayaram
CSIR–Centre for Cellular and Molecular Biology, Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
Sayantan Datta
Tata Institute of Fundamental Research, Hyderabad, India
Ruyu He
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China
Ping Wu
National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai, China
Peng Chao
National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai, China
Ying Zhang
Stowers Institute for Medical Research, Kansas City, United States
Stowers Institute for Medical Research, Kansas City, United States; Department of Cancer Biology, The University of Kansas Medical Center, Kansas City, United States
State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China; Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China
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.
