DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis
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Cellular and Molecular Life Sciences
REVIEW
DYRK1A: a down syndrome‑related dual protein kinase with a versatile role in tumorigenesis Amina Jamal Laham1,2 · Maha Saber‑Ayad1,2 · Raafat El‑Awady1,3 Received: 23 May 2020 / Revised: 22 July 2020 / Accepted: 18 August 2020 © Springer Nature Switzerland AG 2020
Abstract Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual kinase that can phosphorylate its own activation loop on tyrosine residue and phosphorylate its substrates on threonine and serine residues. It is the most studied member of DYRK kinases, because its gene maps to human chromosome 21 within the Down syndrome critical region (DSCR). DYRK1A overexpression was found to be responsible for the phenotypic features observed in Down syndrome such as mental retardation, early onset neurodegenerative, and developmental heart defects. Besides its dual activity in phosphorylation, DYRK1A carries the characteristic of duality in tumorigenesis. Many studies indicate its possible role as a tumor suppressor gene; however, others prove its pro-oncogenic activity. In this review, we will focus on its multifaceted role in tumorigenesis by explaining its participation in some cancer hallmarks pathways such as proliferative signaling, transcription, stress, DNA damage repair, apoptosis, and angiogenesis, and finally, we will discuss targeting DYRK1A as a potential strategy for management of cancer and neurodegenerative disorders. Keywords Carcinogenesis · p53 · RNF169 · 53BP1 · Alzheimer · DNA damage · DNA repair · Cancer therapy
Introduction Phosphorylation is a critical post-translational modification that regulates many cellular processes such as proliferation, apoptosis, differentiation, homeostasis, and metabolism [8, 9]. This modification is introduced by protein kinases that consume adenosine triphosphate (ATP) to add the Ƴ-phosphate group on protein or lipid substrates [12]. According to the phosphorylated residue, kinases can be classified into tyrosine kinases (TKs) and serine/threonine kinase (STKs) [16]. The addition of Phosphate group induces conformational changes to the protein affecting its function through changing its activity, cellular localization, stability, interaction with other proteins, and DNA [12]. * Maha Saber‑Ayad [email protected] * Raafat El‑Awady [email protected] 1
College of Medicine, University of Sharjah, Sharjah, UAE
2
Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
3
College of Pharmacy, University of Sharjah, Sharjah, UAE
Mutation and dysregulation of kinases are implicated in various human diseases such as cancer, metabolic disorder, neurodegeneration, autoimmunity, and cardiovascular diseases [8, 21, 22]. To date, about 538 protein kinases have been identified in human cells that account for 2% of human genes [8]. These kinases are classified into many groups based on sequence homology of their catalytic domains [9]. CMGC (CDKs, MAPK, GSK, CLK) group which is one of the largest groups including 9 k
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