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DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity
Pinhua Wang1, Sunayana Sarkar2, Menghuan Zhang1
1State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China.
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.
Insights
DYRK1A kinase regulates cell growth by inhibiting the TSC complex, promoting mTORC1 activity. This mechanism is conserved in Drosophila, highlighting DYRK1A
Area of Science:
- Cell Biology
- Developmental Biology
- Biochemistry
Background:
- DYRK1A (Dual-specificity Yak-like kinase 1A) is crucial for organ growth but its regulatory mechanisms are unclear.
- DYRK1A is implicated in intellectual disabilities, microcephaly, and Down syndrome.
- DYRK1A influences cell cycle, vesicle trafficking, and microtubule assembly.
Purpose of the Study:
- To elucidate the role of DYRK1A in regulating cell size and organ growth.
- To identify the molecular targets and pathways through which DYRK1A exerts its effects.
- To investigate the conserved function of DYRK1A in growth regulation.
Main Methods:
- Mammalian cell culture and DYRK1A knockdown.
- Proteomic analysis to identify DYRK1A interacting proteins.
- Western blotting to detect protein phosphorylation.
- Drosophila neuromuscular junction assays.
Main Results:
- DYRK1A knockdown in mammalian cells reduced cell size, dependent on mTORC1.
- DYRK1A was found to interact with TSC1/TSC2 complex proteins.
- DYRK1A phosphorylates TSC2 at T1462, inhibiting TSC activity and activating mTORC1.
- Overexpression of RHEB rescued reduced cell growth in DYRK1A knockdown cells and Drosophila mnb mutants.
Conclusions:
- DYRK1A promotes cell growth by inhibiting the TSC complex via phosphorylation of TSC2, thereby activating mTORC1.
- This mechanism of DYRK1A-mediated mTORC1 regulation is conserved from flies to mammals.
- DYRK1A's role in growth regulation offers potential therapeutic targets for related developmental disorders.
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