The Protein Kinase DYRK1A Regulates Caspase-9-Mediated Apoptosis during Retina Development

Abstract

The precise regulation of programmed cell death is critical for the normal development of the nervous system. We show here that DYRK1A (minibrain), a protein kinase essential for normal growth, is a negative regulator of the intrinsic apoptotic pathway in the developing retina. We provide evidence that changes in Dyrk1A gene dosage in the mouse strongly alter the cellularity of inner retina layers and result in severe functional alterations. We show that DYRK1A does not affect the proliferation or specification of retina progenitor cells, but rather regulates the number of cells that die by apoptosis. We demonstrate that DYRK1A phosphorylates caspase-9 on threonine residue 125, and that this phosphorylation event is crucial to protect retina cells from apoptotic cell death. Our data suggest a model in which dysregulation of the apoptotic response in differentiating neurons participates in the neuropathology of diseases that display DYRK1A gene-dosage imbalance effects, such as Down's syndrome.

Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

“…Meanwhile, Dyrk1A negatively regulates intrinsic apoptotic pathway by phosphorylating caspase-9 at Thr-125 during retina development (50). In this system, Dyrk1A had no effect on the proliferation of retina progenitor cells (50), implying that we should further investigate the diverse putative roles of Dyrk1A and its possible link to many different systems.…”

Cellular Mechanisms Controlling Caspase Activation and Function

“…Lying between the CARD domain and the large subunit of caspase-9, phosphorylated Thr125 decreases caspase-9 activation (and consequently decreases its proteolytic processing) through an undefined mechanism (Allan et al 2003). Thr125 was first identified as a site of phosphorylation by the Erk kinase, but more recently, the cyclindependent kinase cdk1, DYRK1A, and p38a have all been reported to phosphorylate caspase-9 at this site, reducing its activation and the downstream activation of caspase-3 (Allan et al 2003;Allan and Clarke 2007;Laguna et al 2008;Seifert et al 2008;Seifert and Clarke 2009) (Fig. 3).…”

MiR-1246: A new link of the p53 family with cancer and Down syndrome

“…First, DYRK1A phosphorylates caspase-9 and inhibits its ability to trigger apoptosis. 26,29,30 Also, DYRK1A binds to and phosphorylates HPV16E7 at threonine 5 and threonine 7, and this phosphorylation makes this oncoprotein much more stable, 31 consequently promoting cell proliferation and growth. Furthermore, DYRK1A has been shown to suppress apoptosis by phosphorylating and activating Sirt1, which, in turn, deacetylates p53 and inactivates its apoptotic activity.…”

“…Since DYRK1A is highly expressed in Down syndrome patients due to trisomy 21 and is shown to promote cell survival and to inhibit apoptosis, 26,28,[31][32][33][34] it would be predicted that these patients might have the high risk of developing cancer. However, the story might not be this simple, as some Down syndrome-associated proteins were also found to induce apoptosis in cells, such as ETS2.…”