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 Blood, 1 December 2004, Vol. 104, No. 12, pp. 3550-3557.
Prepublished online as a Blood First Edition Paper on July 29, 2004; DOI 10.1182/blood-2004-03-1066.

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HEMATOPOIESIS

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, and Toshio Kitamura

From the Division of Cellular Therapy and the Division of Hematopoietic Factors, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

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 transcription–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 ({Delta}GAP) did not significantly enhance it, suggesting that the GAP domain was required for enhancement of STAT3-dependent transcription. Intriguingly, M1 cells expressing {Delta}GAP 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.


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