J. Czyzyk et al., Combinatorial effect of T-cell receptor ligation and CD45 isoform expression on the signaling contribution of the small GTPases Ras and Rap1, MOL CELL B, 20(23), 2000, pp. 8740-8747
By using ligands with various affinities for the T-cell receptor (TCR) and
by altering the contribution of the CD45 tyrosine phosphatase, the effects
of the potency of TCR-induced signals on the function of small GTPases Ras
and Rap1 were studied. T cells expressing low-molecular-weight CD45 isoform
s (e.g., CD45RO) exhibited the strongest activation of the Ras-dependent El
k-1 transcription factor and the highest sensitivity to the inhibitory acti
on of dominant negative mutant Ras compared to T cells expressing high-mole
cular-weight CD45 isoforms (ABC). Moreover, stimulation of CD45RO(+), but n
ot CD45ABC(+), T cells with a high-affinity TCR ligand induced suboptimal E
lk-1 activation compared with the stimulation induced by an intermediate-af
finity TCR-ligand interaction. This observation suggested that the Res-depe
ndent signaling pathway is safeguarded in CD45RO(+) expressors by a negativ
e regulatory mechanism(s) which prohibits maximal activation of the Ras-dep
endent signaling events following high-avidity TCR-ligand engagement. Inter
estingly, the biochemical activity of another small GTPase, the Ras-like pr
otein Rap1, which has been implicated in the functional suppression of Ras
signaling, was inversely correlated with the extent of Elk-1 activation ind
uced by different- affinity TCR ligands. Consistently, overexpression of pu
tative Rap dominant negative mutant RapN17 or the physiologic inhibitor of
Rap1, the Rap GTPase-activating protein RapGAP, augmented the Elk-1 respons
e in CD45RO(+) T cells. This is in contrast to the suppressive effect of Ra
pN17 and RapGAP on CD45ABC(+) T cells, underscoring the possibility that Ra
p1 can act as either a repressor or a potentiator of Res effector signals,
depending on CD45 isoform expression. These observations suggest that cells
expressing distinct isoforms of CD45 employ different signal transduction
schemes to optimize Ras-mediated signal transduction in activated T lymphoc
ytes.