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

32 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
Externally publishedYes

Fingerprint

Guanosine
Transducers
Germ Cells
GTPase-Activating Proteins
Interleukin-6
Chemical activation
Cells
Cell Line
Proteins
Transcription
Macrophages
Cysteine
Assays
RNA Interference
Cell Division
RNA
Transcriptional Activation
Leukemia

ASJC Scopus subject areas

  • Hematology

Cite this

Tonozuka, Y., Minoshima, Y., Bao, Y. C., Moon, Y., Tsubono, Y., Hatori, T., ... Kitamura, T. (2004). A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line. Blood, 104(12), 3550-3557. https://doi.org/10.1182/blood-2004-03-1066

A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line. / Tonozuka, Yukio; Minoshima, Yukinori; Bao, Ying Chun; Moon, Yuseok; Tsubono, Yohei; Hatori, Tomonori; Nakajima, Hideaki; Nosaka, Tetsuya; Kawashima, Toshiyuki; Kitamura, Toshio.

In: Blood, Vol. 104, No. 12, 01.12.2004, p. 3550-3557.

Research output: Contribution to journalArticle

Tonozuka, Y, Minoshima, Y, Bao, YC, Moon, Y, Tsubono, Y, Hatori, T, Nakajima, H, Nosaka, T, Kawashima, T & Kitamura, T 2004, 'A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line', Blood, vol. 104, no. 12, pp. 3550-3557. https://doi.org/10.1182/blood-2004-03-1066
Tonozuka, Yukio ; Minoshima, Yukinori ; Bao, Ying Chun ; Moon, Yuseok ; Tsubono, Yohei ; Hatori, Tomonori ; Nakajima, Hideaki ; Nosaka, Tetsuya ; Kawashima, Toshiyuki ; Kitamura, Toshio. / A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line. In: Blood. 2004 ; Vol. 104, No. 12. pp. 3550-3557.
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AU - Moon, Yuseok

AU - Tsubono, Yohei

AU - Hatori, Tomonori

AU - Nakajima, Hideaki

AU - Nosaka, Tetsuya

AU - Kawashima, Toshiyuki

AU - Kitamura, Toshio

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