Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family phosphorylate many substrates, including critical regulators of the cell cycle. A recent report revealed that human DYRK2 acts as a negative regulator of G1/S transition by phosphorylating c-Jun and c-Myc, thereby inducing ubiquitination-mediated degradation. Other DYRKs also function as cell cycle regulators by modulating the turnover of their target proteins. DYRK1B can induce reversible cell arrest in a quiescent G0 state by targeting cyclin D1 for proteasomal degradation and stabilizing p27 (Kip1). The DYRK2 ortholog of C. elegans, MBK-2, triggers the proteasomal destruction of oocyte proteins after meiosis to allow the mitotic divisions in embryo development. This review summarizes the accumulating results that provide evidence for a general role of DYRKs in the regulation of protein stability.

Figure 1. DYRK2 targets c-Myc for ubiquitination and destruction. Phosphorylation of Ser62 by DYRK2 primes c-Myc for phosphorylation at Thr58 by GSK3β. The resulting phosphodegron motif is recognized by Fbw7, which acts as the substrate receptor of an SCF complex (SKP1/cullin1/Fbw7/Rbx), initiating ubiquitination by the E2 ligase and subsequent proteasomal degradation. Likewise, c-Jun is ubiquitinated after sequential phosphorylation at Thr239 and Ser243 by DYRK2 and GSK3β.