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A Novel Role for H-Ras in the Regulation of Very Late Antigen-4 Integrin and VCAM-1 Via c-Myc-Dependent and -Independent Mechanisms¹

Zhao-Jun Liu^*, Yoshiya Tanaka, Hiroko Fujimoto^*,, Shinichiro Mine, Akio Morinobu^§, Hideo Yagita^¶,||, Ko Okumura^¶,||, Isao Oishi^*, Jun Udagawa^#, Hirohei Yamamura^* and Yasuhiro Minami^2,*

^* Department of Biochemistry, Kobe University School of Medicine, Kobe, Japan; First Department of Internal Medicine, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan; School of Allied Health Science, Faculty of Medicine, Osaka University, Osaka, Japan; ^§ Department of Laboratory Medicine, Kobe University School of Medicine, Kobe, Japan; ^¶ Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; ^|| Core Research for Evolutional Science and Technology of Japan, Science and Technology Corporation, Tokyo, Japan; and ^# Department of Anatomy, Shimane Medical University, Izumo, Japan

Despite extensive studies on the crucial functions of Ras and c-Myc in cellular proliferation and transformation, their roles in regulating cell adhesion are not yet fully understood. Involvement of Ras in modulating integrin activity by inside-out signaling has been recently reported. However, in contrast to R-Ras, H-Ras was found to exhibit a suppressive effect. Here we show that ectopic expression of a constitutively active H-Ras^v12, but not c-Myc alone, in a hemopoietic cell line induces activation of very late Ag-4 (VLA-4, ₄ß₁) integrin without changing its surface expression. Intriguingly, coexpression of H-Ras^v12 and c-Myc in these cells results in not only the activation of VLA-4, but also the induction of expression of VCAM-1, the counterreceptor for VLA-4, thereby mediating a marked homotypic cell aggregation. In addition, H-Ras^v12-induced VLA-4 activation appears to be partly down-regulated by coexpression with c-Myc. Our results represent an unprecedented example demonstrating a novel role for H-Ras^v12 in the regulation of cell adhesion via c-Myc-independent and -dependent mechanisms.

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