p21ras couples the T cell antigen receptor to extracellular signal-regulated kinase 2 in T lymphocytes.
It has previously been shown in T cells that stimulation of protein kinase C (PKC) or the T cell antigen receptor (TCR) induces the rapid accumulation of the active guanosine triphosphate-bound form of p21ras. These stimuli also induce the activation of extracellular signal-regulated kinase 2 (ERK2), a serine/threonine kinase that is rapidly activated via a kinase cascade in response to a variety of growth factors in many cell types. In this study, we show that p21ras is a component of the TCR signaling pathway that controls ERK2 activation. In the human Jurkat T cell line, transient expression of constitutively active p21ras induces ERK2 activation, measured as an increase in the ability of an ERK2-tag reporter protein to phosphorylate myelin basic protein. Thus, constitutively active p21ras bypasses the requirement for PKC activation or TCR triggering to induce ERK2 activation. In addition, activation of PKC or the TCR produces signals that cooperate with activated p21ras to stimulate ERK2. Conversely, expression of a dominant negative mutant of ras, Ha-ras N17, blocks ERK2 activation after TCR stimulation, indicating that endogenous p21ras function is necessary for the TCR-stimulated ERK2 activation. Taken together, these results demonstrate that the activation of p21ras is both necessary and sufficient to induce ERK2 activation in T cells.
Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London, UK.
M
M
Izquierdo
S J
SJ
Leevers
C J
CJ
Marshall
D
D
Cantrell
D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D011948:Receptors, Antigen, T-Cell; D015240:Phorbol 12,13-Dibutyrate; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; C501009:HRAS protein, human; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras)