The STAT3 beacon: IL-6 recurrently activates STAT 3 from endosomal structures

Christopher L. German, Brian M. Sauer, Charles L Howe

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Endocytic trafficking plays an important role in signal transduction. Signal transducer and activator of transcription 3 (STAT3) and mitogen-activate protein kinase (MAPK) have both been localized to endosomal structures and are dependent upon endocytosis for downstream function. While the dependence of MAPK signaling upon endosomes has been well characterized, the involvement of endosomes in regulating STAT3 signaling has not been defined. Consequently, this study evaluated the role of endosomes in the initiation, modulation, amplification and persistence of interleukin-6(IL-6)-induced STAT3 signal transduction and transcription, and utilized IL-6-induced MAPK signaling as a comparator. Using pharmacologic treatment and temperature control of endocytic trafficking, pulse-chase treatments and in vitro kinase assays, STAT3 was found to interact with endosomes in a markedly different fashion than MAPK. STAT3 was activated by direct interaction with internal structures upstream of the late endosome following IL-6 exposure and persistent STAT3 signaling depended upon recurrent activation from endocytic structures. Further, STAT3 subcellular localization was not dependent upon endocytic trafficking. Instead, STAT3 transiently interacted with endosomes and relocated to the nucleus by an endosome-independent mechanism. Finally, endocytic trafficking played a central role in regulating STAT3 serine 727 phosphorylation through crosstalk with the MAPK signaling system. Together, these data reveal endosomes as central to the genesis, course and outcome of STAT3 signal transduction and transcription.

Original languageEnglish (US)
Pages (from-to)1955-1969
Number of pages15
JournalExperimental Cell Research
Volume317
Issue number14
DOIs
StatePublished - Aug 15 2011

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Keywords

  • Erk1/2
  • IL-6
  • MAPK
  • Signaling endosome
  • STAT3

ASJC Scopus subject areas

  • Cell Biology

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