SUMOylation regulates nuclear accumulation and signaling activity of the soluble intracellular domain of the ErbB4 receptor tyrosine kinase

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: Anna M. Knittle, Maria Helkkula, Mark S. Johnson, Maria Sundvall, Klaus Elenius
Förläggare: American Society for Biochemistry and Molecular Biology, Inc.
Förlagsort: USA
Publiceringsår: 2017
Tidskrift: Journal of Biological Chemistry
Tidskriftsakronym: JBC
Volym: 292
Nummer: 48
Artikelns första sida, sidnummer: 19890
Artikelns sista sida, sidnummer: 19904
eISSN: 1067-8816


Abstrakt







Erb-B2 receptor tyrosine kinase 4 (ErbB4) is a kinase that can
signal via a proteolytically released intracellular domain (ICD)
in addition to classical receptor tyrosine kinase–activated sig-
naling cascades. Previously, we have demonstrated that ErbB4
ICD is posttranslationally modified by the small ubiquitin-like
modifier (SUMO) and functionally interacts with the PIAS3
SUMO E3 ligase. However, direct evidence of SUMO modifica-
tion in ErbB4 signaling has remained elusive. Here, we report
that the conserved lysine residue 714 in the ErbB4 ICD under-
goes SUMO modification, which was reversed by sentrin-spe-
cific proteases (SENPs) 1, 2, and 5. Although ErbB4 kinase activ-
ity was not necessary for the SUMOylation, the SUMOylated
ErbB4 ICD was tyrosine phosphorylated to a higher extent than
unmodified ErbB4 ICD. Mutation of the SUMOylation site com-
promised neither ErbB4-induced phosphorylation of the canon-
ical signaling pathway effectors Erk1/2, Akt, or STAT5 nor
ErbB4 stability. In contrast, SUMOylation was required for
nuclear accumulation of the ErbB4 ICD. We also found that
Lys-714 was located within a leucine-rich stretch, which resem-
bles a nuclear export signal, and could be inactivated by site-
directed mutagenesis. Furthermore, SUMOylation modulated
the interaction of ErbB4 with chromosomal region maintenance
1 (CRM1), the major nuclear export receptor for proteins.
Finally, the SUMO acceptor lysine was functionally required for
ErbB4 ICD-mediated inhibition of mammary epithelial cell dif-
ferentiation in a three-dimensional cell culture model. Our find-
ings indicate that a SUMOylation-mediated mechanism regu-
lates nuclear localization and function of the ICD of ErbB4





Nyckelord

EGFR, signalling, SUMO

Senast uppdaterad 2019-15-11 vid 05:20