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 cell ular proliferation and transformation, their roles in regulating cell adhes ion are not yet fully understood. Involvement of Ras in modulating integrin activity by inside-out signaling has been recently reported. However, in c ontrast 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 very la te Ag-4 (VLA-4, alpha(4)beta(1)) integrin without changing its surface expr ession. Intriguingly, coexpression of H-Ras(v12) and c-Myc in these cells r esults in not only the activation of VLA-4, but also the induction of expre ssion of VCAM-1, the counterreceptor for VLA-4, thereby mediating a marked homotypic cell aggregation. In addition, H-Ras(v12)-induced VLA-4 activatio n appears to be partly down-regulated by coexpression with c-Myc. Our resul ts represent an unprecedented example demonstrating a novel role for H-Ras( v12) in the regulation of cell adhesion via c-Myc-independent and -dependen t mechanisms.