The Conserved Transcriptional Activation Activity Identified in Dual-Specificity

Xiuke Ouyang1, Zhuqing Wang1, Bingtong Wu1

  • 1Fang Zongxi Center, MoE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.

Biomolecules
|February 25, 2023
PubMed

Insights

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 (DYRK1) has a novel function beyond its kinase activity. This protein kinase also acts as a transcription factor, regulating genes involved in neuronal function and intellectual disability.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 (DYRK1) is crucial for neuron development.
  • The non-kinase functions of DYRK1 are not well understood.

Purpose of the Study:

  • To investigate potential non-kinase functions of DYRK1.
  • To identify conserved functional domains and regulatory mechanisms of DYRK1.
  • To explore the role of DYRK1's transcriptional activity in neurodevelopmental disorders.

Main Methods:

  • Analysis of ascidian Ciona robusta DYRK1 (CrDYRK1) and human HsDYRK1A.
  • Assessment of transcriptional activation and repression activities.
  • Identification of target genes and DNA motifs using transcriptome data.
  • Examination of mutation sites associated with intellectual disability.

Main Results:

  • CrDYRK1 possesses C-terminal transcriptional activation activity independent of its kinase function.
  • N-terminal repression domain autoinhibits DYRK1's activation.
  • HsDYRK1A retains both activation and repression domains, regulating genes involved in ion transport and neuroactive ligand-receptor interactions.
  • Mutation sites for DYRK1A-related intellectual disability syndrome are located in the C-terminal domain.

Conclusions:

  • DYRK1 possesses a conserved transcription activation domain in urochordates and vertebrates.
  • This transcriptional activity is independent of kinase function and subject to autoinhibition.
  • DYRK1's transcriptional role is implicated in synaptic transmission and neuronal function relevant to intellectual disability.

Related Concept Videos

Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
13.4K
RNA Polymerase II Accessory Proteins02:36

RNA Polymerase II Accessory Proteins

Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
9.3K
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
7.4K
Eukaryotic Transcription Activators02:42

Eukaryotic Transcription Activators

Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
11.2K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.8K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.8K