DYRK1A Interacts with the Tuberous Sclerosis Complex and Promotes mTORC1 Activity

Author:

Wang Pinhua1,Sarkar Sunayana2,Zhang Menghuan1,Xiao Tingting1,Kong Fenhua1,Zhang Zhe1,Balasubramanian Deepa2,Jayaram Nandan3,Datta Sayantan2ORCID,He Ruyu1,Wu Ping4,Chao Peng4ORCID,Zhang Ying5,Washburn Michael P56ORCID,Florens Laurence5,Nagarkar-Jaiswal Sonal3,Jaiswal Manish2,Mohan Man17ORCID

Affiliation:

1. State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology

2. Tata Institute of Fundamental Research, Hyderabad

3. CSIR–Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road Hyderabad

4. National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai

5. Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City

6. Department of Cancer Biology, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City

7. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine

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 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. Further, 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. Further, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologues of DYRK1A , is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.

Publisher

eLife Sciences Publications, Ltd

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