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J. Biol. Chem., Vol. 279, Issue 40, 42279-42289, October 1, 2004

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Disabled-2 Is a Negative Regulator of Integrin _IIb3-mediated Fibrinogen Adhesion and Cell Signaling^*

Chien-Ling Huang, Ju-Chien Cheng, Chang-Hui Liao¶, Arnold Stern||, Jer-Tsong Hsieh**, Chi-Huei Wang, Hsueh-Ling Hsu, and Ching-Ping Tseng

From the Graduate Institutes of Medical Biotechnology and ^¶Natural Products, Chang Gung University, Tao-Yuan 333, Taiwan, Republic of China, the Department of Medical Technology, China Medical University, Taichung 404, Taiwan, Republic of China, the ^||Department of Pharmacology, New York University School of Medicine, New York, New York 10016, the ^**Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, and the Faculty of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China

Disabled-2 (DAB2) is an adapter protein that is up-reg-ulated during megakaryocytic differentiation of hematopoietic cells and is abundantly expressed in platelets. In this study, the role of DAB2 in integrin _IIb3-mediated matrix protein fibrinogen adhesion and cell signaling was investigated. In K562 cells differentiating to the megakaryocytic lineage, down-regulation of DAB2 by DAB2 small interfering RNA augmented integrin _IIb3 activation and resulted in an increase in cell adhesion to fibrinogen. Ectopic expression of DAB2 reversed the DAB2 small interfering RNA effect or, by itself, decreased fibrinogen adhesion of K562 cells. Mutational analysis revealed that a DAB2 Ser²⁴ phosphorylation mutant (S24A) abrogated the inhibitory function of DAB2. The spatial and temporal association/interaction of DAB2 and platelet integrin _IIb3 (CD61) in both megakaryocytic cells and platelets led us to examine the effect of Ser²⁴ phosphorylation on the interaction between DAB2 and integrin ₃. Through cellular localization and co-immunoprecipitation analysis, we demonstrate for the first time that Ser²⁴ phosphorylation promotes membrane translocation of DAB2 and its subsequent interaction with integrin ₃, thereby defining a mechanism for DAB2 in regulating integrin _IIb3 activation and inside-out signaling. Consistent with the effect on fibrinogen adhesion, Ser²⁴ phosphorylation of DAB2 was also involved in the negative regulation of _IIb3-induced T cell factor transcriptional activity. In contrast, the S24A mutant acted like wild-type DAB2 and inhibited both -catenin- and plakoglobin-mediated T cell factor transactivation. Hence, DAB2 elicits distinct regulatory mechanisms in _IIb3 and -catenin/plakoglobin signaling in a Ser²⁴ phosphorylation-dependent and -independent manner, respectively. These findings indicate Ser²⁴ phosphorylation as a molecular basis for DAB2 acting as a negative regulator in _IIb3 inside-out signaling and contribute to our understanding of DAB2 in megakaryocytic differentiation and platelet function.

Received for publication, March 5, 2004 , and in revised form, July 23, 2004.

^* This work was supported in part by National Science Council Grant NSC 92-2314-B-182-061 and NSC 93-2314-B-182-072 and Chang Gung Memorial Hospital Grant CMRP1206 (to C.-P. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Graduate Inst. of Medical Biotechnology, Chang Gung University, 259 Wen-Hwai 1st Rd., Kwei-Shen, Tao-Yuan 333, Taiwan, Republic of China. Tel.: 3-211-8800 (ext. 5202); Fax: 3-211-8355; E-mail: ctseng{at}mail.cgu.edu.tw.

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