# DYRK1A interaction network in development and disease

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $413,529

## Abstract

Summary: DYRKA1 (Dual-specificity tyrosine-regulated kinase 1A) is a gene within the critical region of
chromosome 21, and excess of the encoded protein is thought to contribute to many facets of the Down
Syndrome associated birth defects, including craniofacial anomalies. Modulating the function of DYRK1A in utero
has been proposed as a method to improve outcomes for children with Down Syndrome. However, unrestricted
inhibition of this protein kinase poses major concerns since DYRK1A is a tumor suppressor. Therefore, we ideally
need to develop the tools that can more precisely manipulate DYRK1A during embryonic development without
causing harmful side effects. We have identified two proteins, LZTS2 and SIPA1L1, that form a novel regulatory
complex with DYRK1A. The broad goal of this exploratory project is to test whether these two NEW candidate
DYRK1A regulators can indeed modulate the function of this important kinase in the embryo. We propose to
integrate the use of biochemical assays in human cells and in vivo studies in the developmental model, Xenopus
laevis, to better understand the molecular effects of LZTS2 and SIPA1L1 on DYRK1A function. Xenopus
homologues of these three proteins display high sequence identity to their human counterparts, including Lzts2
(50.2%), Sipa1l1 (75.9%) and Dyrk1a (92.4%). Our preliminary studies and published literature implicate each
of these proteins into developmental processes in various organisms. However, the physiological significance of
their interaction has not been investigated in any model system. Here, we propose to fill this knowledge gap as
a first step towards the understanding and potentially alleviating the craniofacial abnormalities associated with
Down syndrome. In Aim1 we will determine if Lzts2 and Sipa1l1 interact with Dyrk1a during craniofacial
development in Xenopus. We will assess whether Lzts2, Sipa1l1 and Dyrk1a are in the same pathway using a
phenotypic modifier assay. Then, we will determine whether modifying the levels of these proteins can alter the
activity of Dyrk1a in the embryo using an in vitro approach developed in the Litovchick lab. Also, with the aim of
developing Xenopus as a tool for Down syndrome research we will ask whether inhibition of Lzts2 and/or Sipa1l1
can compensate for Dyrk1a excess. In Aim 2 we will characterize mechanisms of LZTS2 and SIPA1L1 mediated
regulation of DYRK1A in mammalian cells and validate our findings in embryos. Preliminary data in human cells
indicates that LZTS2 promotes DYRK1A activity, possibly by enhancing phosphorylation of DYRK1A at a novel
site by unknown mechanism. We will extend these data by testing whether SIPA1L1 is required for LZTS2
mediated activity and phosphorylation. We will explore the nature of this and other modifications of DYRK1A that
require LZTS2 and SIPA1L1. Finally, in this aim, the role of the LZTS2-SIPA1L1-regulated phosphorylation
site(s) will also be explored in embryos. The outcomes of this study will set the...

## Key facts

- **NIH application ID:** 10373183
- **Project number:** 1R21HD105144-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Amanda Jane Dickinson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $413,529
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373183

## Citation

> US National Institutes of Health, RePORTER application 10373183, DYRK1A interaction network in development and disease (1R21HD105144-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10373183. Licensed CC0.

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