CD28 and the tyrosine kinase lck stimulate mitogen-activated protein kinase activity in T cells via inhibition of the small G protein Rap1.
Proliferation of T cells via activation of the T-cell receptor (TCR) requires concurrent engagement of accessory costimulatory molecules to achieve full activation. The best-studied costimulatory molecule, CD28, achieves these effects, in part, by augmenting signals from the TCR to the mitogen-activated protein (MAP) kinase cascade. We show here that TCR-mediated stimulation of MAP kinase extracellular-signal-regulated kinases (ERKs) is limited by activation of the Ras antagonist Rap1. CD28 increases ERK signaling by blocking Rap1 action. CD28 inhibits Rap1 activation because it selectively stimulates an extrinsic Rap1 GTPase activity. The ability of CD28 to stimulate Rap1 GTPase activity was dependent on the tyrosine kinase Lck. Our results suggest that CD28-mediated Rap1 GTPase-activating protein activation can help explain the augmentation of ERKs during CD28 costimulation.
Carey
K D
KD
Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Dillon
T J
TJ
Schmitt
J M
JM
Baird
A M
AM
Holdorf
A D
AD
Straus
D B
DB
Shaw
A S
AS
Stork
P J
PJ
D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains
D018106:CD28 Antigens; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020929:Mitogen-Activated Protein Kinase Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one