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

Anna M. Knittle, Maria Helkkula, Mark S Johnson, Maria Sundvall, Klaus Elenius

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14 Citations (Scopus)


Erb-B2 receptor tyrosine kinase 4 (ErbB4) is a kinase that cansignal via a proteolytically released intracellular domain (ICD)in addition to classical receptor tyrosine kinase–activated sig-naling cascades. Previously, we have demonstrated that ErbB4ICD is posttranslationally modified by the small ubiquitin-likemodifier (SUMO) and functionally interacts with the PIAS3SUMO E3 ligase. However, direct evidence of SUMO modifica-tion in ErbB4 signaling has remained elusive. Here, we reportthat 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 SUMOylatedErbB4 ICD was tyrosine phosphorylated to a higher extent thanunmodified 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 norErbB4 stability. In contrast, SUMOylation was required fornuclear accumulation of the ErbB4 ICD. We also found thatLys-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 modulatedthe interaction of ErbB4 with chromosomal region maintenance1 (CRM1), the major nuclear export receptor for proteins.Finally, the SUMO acceptor lysine was functionally required forErbB4 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 

Original languageUndefined/Unknown
Pages (from-to)19890–19904
JournalJournal of Biological Chemistry
Issue number48
Publication statusPublished - 2017
MoE publication typeA1 Journal article-refereed


  • signalling
  • EGFR
  • SUMO

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