The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2.

Florian Glenewinkel,Cason R King,Joe S Mymryk,Walter Becker,Sophie Kaspar,Simone Bamberg-Lemper,Michael J Cohen

doi:10.1038/srep28241

Florian Glenewinkel, Cason R King + Show 5 more

Open Access

https://doi.org/10.1038/srep28241

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Journal: Scientific Reports	Publication Date: Jun 16, 2016
Citations: 39	License type: CC BY 4.0

Affiliation: RWTH Aachen University, Western University

Abstract

DYRK1A is a constitutively active protein kinase that has a critical role in growth and development which functions by regulating cell proliferation, differentiation and survival. DCAF7 (also termed WDR68 or HAN11) is a cellular binding partner of DYRK1A and also regulates signalling by the protein kinase HIPK2. DCAF7 is an evolutionarily conserved protein with a single WD40 repeat domain and has no catalytic activity. We have defined a DCAF7 binding motif of 12 amino acids in the N-terminal domain of class 1 DYRKs that is functionally conserved in DYRK1 orthologs from Xenopus, Danio rerio and the slime mold Dictyostelium discoideum. A similar sequence was essential for DCAF7 binding to HIPK2, whereas the closely related HIPK1 family member did not bind DCAF7. Immunoprecipitation and pulldown experiments identified DCAF7 as an adaptor for the association of the adenovirus E1A protein with DYRK1A and HIPK2. Furthermore, DCAF7 was required for the hyperphosphorylation of E1A in DYRK1A or HIPK2 overexpressing cells. Our results characterize DCAF7 as a substrate recruiting subunit of DYRK1A and HIPK2 and suggest that it is required for the negative effect of DYRK1A on E1A-induced oncogenic transformation.

Highlights

DCAF7 is a WD40 domain protein that was discovered in a preparation of DYRK1A from rabbit skeletal muscle[10]
We show that DCAF7 binds to early region 1A (E1A) and acts as an essential adaptor protein that mediates the interaction of DYRK1A and HIPK2 with E1A
Zebrafish DYRK1B has been reported to interact with the orthologous DCAF7 protein, suggesting that the binding interface between DCAF7 and class 1 DYRKs is conserved in evolution

Summary

Introduction

DCAF7 ( designated HAN11 or WDR68) is a WD40 domain protein that was discovered in a preparation of DYRK1A from rabbit skeletal muscle[10]. DCAF7 is the gene symbol assigned by the Human Gene Nomenclature Committee, meaning “DDB1 and CUL4 associated factor 7” This name refers to the identification of the protein in DDB1 complexes and the deduced function as a substrate receptor in CLR4 E3 ubiquitin ligase complexes (CUL4–RBX1–DDB1)[13]. CG14614 associates with the Drosophila DYRK1 ortholog, MNB (encoded by the minibrain gene, mnb), and both genes were shown to control normal wing and leg growth by modulating the Salvador-Wart-Hippo (SWH) pathway[22] These results from zebrafish and Drosophila provide evidence that the interaction of class 1 DYRKs with DCAF7 is functionally important in the modulation of pathways involved in differentiation and proliferation. We show that DCAF7 binds to E1A and acts as an essential adaptor protein that mediates the interaction of DYRK1A and HIPK2 with E1A

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