INTERLEUKIN-4-DEPENDENT PROLIFERATION DISSOCIATES P44(ERK-1), P42(ERK-2) AND P21(RAS) ACTIVATION FROM CELL-GROWTH

The activation of erk/mitogen-activated protein kinases and p21(ras) is strongly associated with progression through the cell cycle. Cell growth induced by the cytokine interleukin-4 (IL-4) effectively dissociates the activation of p44(erk-1) and p42(erk-2) mitogen-activated protein kinases and p21(ras) from cell proliferation. In two cell lines of T lymphocyte and myeloid origin that were dependent upon IL-4 for continuous growth, IL-4 failed to detectably activate or induce tyrosine phosphorylation of p44(erk-1) and p42(erk-2). The activation of p21(ras) was also not detectably affected by IL-4 treatment of these cells. Treatment of the same cells with other growth factors (colony-stimulating factor-1 and Steel factor) or phorbol esters induced the tyrosine phosphorylation and activation of p44(erk-1) and p42(erk-2) and stimulated p21(ras) activity. The presence of IL-4 neither diminished nor enhanced the activation of p44(erk-1) and p42(erk-2) by colony-stimulating factor 1, Steel factor, or 12-O-tetradecanoylphorbol-13-acetate. Furthermore, IL-4 also failed to activate p44(erk-1), p42(erk-2), and p21(ras) in normal T lymphocytes and mast cells derived from spleen and bone marrow, respectively. Significantly, these findings demonstrate that IL-4-induced cell growth may be dissociated from the activation of p44(erk-1), p42(erk-2), and p21(ras), suggesting that their activation may not be an absolute requirement for growth factor-stimulated mitogenesis.