A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line

Yukio Tonozuka, Yukinori Minoshima, Ying Chun Bao, Yuseok Moon, Yohei Tsubono, Tomonori Hatori, Hideaki Nakajima, Tetsuya Nosaka, Toshiyuki Kawashima, Toshio Kitamura

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

We previously identified a guanosine triphosphatase (GTPase)-activating protein (GAP) male germ cell Rac GAP (MgcRacGAP) that enhanced interleukin-6 (IL-6)-induced macrophage differentiation of murine M1 leukemia cells. Later, MgcRacGAP was found to play crucial roles in cell division. However, how MgcRacGAP enhanced IL-6-induced differentiation remained elusive. Here we show that MgcRacGAP enhances IL-6-induced differentiation through enhancement of signal transducer and activator of transcripiton-3 (STAT3) activation. MgcRacGAP, Rac, and STAT3 formed a complex in IL-6-stimulated M1 cells, where MgcRacGAP interacted with Rac1 and STAT3 through its cysteine-rich domain and GAP domain. In reporter assays, the wild-type MgcRacGAP enhanced transcriptional activation of STAT3 while a GAP-domain deletion mutant (ΔGAP) did not significantly enhance it, suggesting that the GAP domain was required for enhancement of STAT3-dependani transcription. Intriguingly, M1 cells expressing ΔGAP had no effect on the differentiation signal of IL-6, while forced expression of MgcRacGAP rendered M1 cells hyperresponsive to the IL-6-induced differentiation. Moreover, knockdown of MgcRacGAP by RNA interference profoundly suppressed STAT3 activation, implicating MgcRacGAP in the STAT3-dependent transcription. All together, our data not only reveal an important role for MgcRacGAP in STAT3 activation, but also demonstrate that MgcRacGAP regulates IL-6-induced cellular differentiation in which STAT3 plays a pivotal role.

Original languageEnglish
Pages (from-to)3550-3557
Number of pages8
JournalBlood
Volume104
Issue number12
DOIs
Publication statusPublished - 2004 Dec 1

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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