Functional regulation of DYRK1A, a kinase intimately involved in Down syndrome and autism spectrum disorder, by cellular binding partners
Pr Yoshihiko MIYATA
Department of Cell & Developmental Biology, Graduate School of Biostudies, Kyoto University, Japon
mardi 20 novembre 2018 - 14h00
- Auditorium, IGBMC
Invité(e) par Yann HERAULT
Down syndrome is one of the most common chromosome abnormalities in human and the most common cause of congenital mental impairment. Down syndrome is caused by chromosome 21 trisomy, and a protein kinase, DYRK1A, is encoded in the chromosome 21 critical region. DYRK1A is a human ortholog of Drosophila minibrain gene, and overexpression of DYRK1A is at least partly responsible for the pleiotropic phenotypes observed in Down syndrome patients. Recently, a strong connection between DYRK1A gene mutations and autism spectrum disorder has been revealed. Blood cancers are more common in Down syndrome children, and Down syndrome is associated with an increased risk of Alzheimer disease, implying that DYRK1A might also be involved in tumor biology and neurodegenerative diseases. We identified biochemically cellular proteins that specifically associate with DYRK1A and related DYRKs. A major DYRK1A-binding partner is WDR68, an evolutionarily conserved WD40-repeat protein. WDR68 was originally identified in petunia as a factor controlling the flower color pigment. We have revealed the physiological importance of WDR68 and its interaction with DYRK1A. In addition, we have shown involvement of TRiC/CCT molecular chaperone in forming the DYRK1A-WDR68 complex. Moreover, specific binding of a set of molecular chaperones Hsp90, Cdc37, and Hsp70 are required for solubility and stability of DYRK family protein kinases. The importance of the binding partners of DYRKs for their physiological functions, and future perspectives on DYRK1A studies for understanding the molecular mechanism of mental disorders will be discussed.