Dyrk1A Potentiates Steroid Hormone-Induced Transcription via the Chromatin Remodeling Factor Arip4

Abstract

Dyrk1A, a mammalian homolog of the Drosophila minibrain gene, encodes a dual-specificity kinase, involved in neuronal development and in adult brain physiology. In humans, a third copy of DYRK1A is present in Down syndrome (trisomy 21) and has been implicated in the etiology of mental retardation. To further understand this pathology, we searched for Dyrk1A-interacting proteins and identified Arip4 (androgen receptor-interacting protein 4), a SNF2-like steroid hormone receptor cofactor. Mouse hippocampal and cerebellar neurons coexpress Dyrk1A and Arip4. In HEK293 cells and hippocampal neurons, both proteins are colocalized in a speckle-like nuclear subcompartment. The functional interaction of Dyrk1A with Arip4 was analyzed in a series of transactivation assays. Either Dyrk1A or Arip4 alone displays an activating effect on androgen receptor-and glucocorticoid receptor-mediated transactivation, and Dyrk1A and Arip4 together act synergistically. These effects are independent of the kinase activity of Dyrk1A. Inhibition of endogenous Dyrk1A and Arip4 expression by RNA interference showed that both proteins are necessary for the efficient activation of androgen receptorand glucocorticoid receptor-dependent transcription. As Dyrk1A is an activator of steroid hormone-regulated transcription, the overexpression of DYRK1A in persons with Down syndrome may cause rather broad changes in the homeostasis of steroid hormone-controlled cellular events.

DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

“…Similarly, DYRK1A has been shown to stimulate FKHR-mediated transactivation of the glucose-6-phosphatase gene independently of its kinase activity (von Groote-Bidlingmaier et al, 2003). More recently, DYRK1A was found to stimulate steroid hormone-induced transactivation by interacting with Arip4 in a kinase-independent manner (Sitz et al, 2004). Although DYKR1A has been shown to phosphorylate several proteins in vitro (reviewed in Galceran et al, 2003;Hämmerle et al, 2003b), these findings suggest that DYRK1A also may possess kinase-independent biological functions.…”

“…Moreover, DYRK1A increases FKHR-dependent glucose-6-phosphatase gene expression in hepatoma cells (von Groote-Bidlingmaier et al, 2003). DYRK1A also was recently shown to interact with Arip4 (androgen receptorinteracting protein 4), a steroid hormone receptor cofactor, and it regulates steroid hormone-induced transcription (Sitz et al, 2004). In immortalized hippocampal progenitor cells stimulated by the basic fibroblast growth factor (bFGF), DYRK1A has been shown to be activated by bFGF and stimulate the phosphorylation of the cAMP response-element binding protein to subsequently induce cAMP response element-mediated gene transcription (Yang et al, 2001).…”

Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A

“…Furthermore, DYRK1A can activate some substrates in the absence of detectable kinase activity (Sitz et al, 2004;Kelly and Rahmani, 2005), and the K188R substitution in its ATP binding motif abolishes most of its kinase activity while retaining these other kinase-independent functions (Wiechmann et al, 2003). This K188R substitution did not significantly repress the output of Notch signalling in SH-SY5Y cells following Jagged 1 activation ( Fig.…”

“…Heterozygous mouse mutants also show specific alterations in the brain and overexpression of Dyrk1a causes developmental defects (Fotaki et al, 2002;Hammerle et al, 2003a), strikingly at sites where Notch signalling influences development. Like other members of the family, DYRK1A can modify transcription factors, chromatin remodelling proteins, or components of signalling cascades such as Ras-BRaf-MEK1 (Galceran et al, 2003;von Groote-Bidlingmaier et al, 2003;Sitz et al, 2004;Kelly and Rahmani, 2005;Arron et al, 2006;Gwack et al, 2006). Notch signalling is controlled at several regulatory checkpoints that include ligand and receptor expression, localization, posttranscriptional modification, trafficking or nuclear association, and stability.…”

The expression of the testis-specific Dyrk4 kinase is highly restricted to step 8 spermatids but is not required for male fertility in mice

“…Functional data indicate an involvement of Dyrk1A in Down syndrome (Altafaj, Dierssen et al 2001) and Dyrk1B in survival of cancer cells (Mercer and Friedman 2006), both by phosphorylation and regulation of transcription factors (Woods, Cohen et al 2001;von Groote-Bidlingmaier, Schmoll et al 2003;Sitz, Tigges et al 2004). …”