A novel role for H-Ras in the regulation of very late antigen-4 integrin and VCAM-1 via c-Myc-dependent and -independent mechanisms.
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-Rasv12, but not c-Myc alone, in a hemopoietic cell line induces activation of very late Ag-4 (VLA-4, alpha4beta1) integrin without changing its surface expression. Intriguingly, coexpression of H-Rasv12 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-Rasv12-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-Rasv12 in the regulation of cell adhesion via c-Myc-independent and -dependent mechanisms.
Liu
Z J
ZJ
Department of Biochemistry, Kobe University School of Medicine, Japan.
Tanaka
Y
Y
Fujimoto
H
H
Mine
S
S
Morinobu
A
A
Yagita
H
H
Okumura
K
K
Oishi
I
I
Udagawa
J
J
Yamamura
H
H
Minami
Y
Y
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D005353:Fibronectins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism* / Q000502:physiology; D016029:Receptors, Very Late Antigen / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology
D000276:Adjuvants, Immunologic; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D016271:Proto-Oncogene Proteins c-myc; D016201:Receptors, Lymphocyte Homing; D016029:Receptors, Very Late Antigen; D019010:Vascular Cell Adhesion Molecule-1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)