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ARTD10 substrate identification on protein microarrays: Regulation of GSK3β by mono-ADP-ribosylation.
Cell Commun. Signal. 11:5 (2013)
Background: Although ADP-ribosylation has been described five decades ago, only recently a distinction has been made between eukaryotic intracellular poly- and mono-ADP-ribosylating enzymes. Poly-ADP-ribosylation by ARTD1 (formerly PARP1) is best known for its role in DNA damage repair. Other polymer forming enzymes are ARTD2 (formerly PARP2), ARTD3 (formerly PARP3) and ARTD5/6 (formerly Tankyrase 1/2), the latter being involved in Wnt signaling and regulation of 3BP2. Thus several different functions of poly-ADP-ribosylation have been well described whereas intracellular mono-ADP-ribosylation is currently largely undefined. It is for example not known which proteins function as substrate for the different mono-ARTDs. This is partially due to lack of suitable reagents to study mono-ADP- ribosylation, which limits the current understanding of this post-translational modification. Results: We have optimized a novel screening method employing protein microarrays, ProtoArrays (R), applied here for the identification of substrates of ARTD10 (formerly PARP10) and ARTD8 (formerly PARP14). The results of this substrate screen were validated using in vitro ADP-ribosylation assays with recombinant proteins. Further analysis of the novel ARTD10 substrate GSK3 beta revealed mono-ADP- ribosylation as a regulatory mechanism of kinase activity by non-competitive inhibition in vitro. Additionally, manipulation of the ARTD10 levels in cells accordingly influenced GSK3 beta activity. Together these data provide the first evidence for a role of endogenous mono-ADP- ribosylation in intracellular signaling. Conclusions: Our findings indicate that substrates of ADP-ribosyltransferases can be identified using protein microarrays. The discovered substrates of ARTD10 and ARTD8 provide the first sets of proteins that are modified by mono-ADP-ribosyltransferases in vitro. By studying one of the ARTD10 substrates more closely, the kinase GSK3 beta, we identified mono-ADP- ribosylation as a negative regulator of kinase activity.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Artd ; Posttranslational Modification ; Adp-ribosyltransferase ; Parp10 ; Parp14 ; Artd8 ; Nad(+) ; Kinase Activity ; Regulation; Poly(adp-ribose) Glycohydrolase ; Structural Basis ; Mammalian-cells ; Dna-repair ; Mechanism ; Activation ; Chromatin ; Ubiquitin ; Kinase ; Parp10
ISSN (print) / ISBN
1478-811X
e-ISSN
1478-811X
Zeitschrift
Cell Communication and Signaling
Quellenangaben
Band: 11,
Heft: 1,
Artikelnummer: 5
Verlag
BioMed Central
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Molecular Immunology (IMI)