The small GTPase, Rap1, mediates CD31-induced integrin adhesion.
Integrin-mediated leukocyte adhesion is a critical aspect of leukocyte function that is tightly regulated by diverse stimuli, including chemokines, antigen receptors, and adhesion receptors. How cellular signals from CD31 and other adhesion amplifiers are integrated with those from classical mitogenic stimuli to regulate leukocyte function remains poorly understood. Here, we show that the cytoplasmic tail of CD31, an important integrin adhesion amplifier, propagates signals that induce T cell adhesion via beta1 (VLA-4) and beta2 (LFA-1) integrins. We identify the small GTPase, Rap1, as a critical mediator of this effect. Importantly, CD31 selectively activated the small Ras-related GTPase, Rap1, but not Ras, R-Ras, or Rap2. An activated Rap1 mutant stimulated T lymphocyte adhesion to intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as did the Rap1 guanine nucleotide exchange factor C3G and a catalytically inactive mutant of RapGAP. Conversely, negative regulators of Rap1 signaling blocked CD31-dependent adhesion. These findings identify a novel important role for Rap1 in regulating ligand-induced cell adhesion and suggest that Rap1 may play a more general role in coordinating adhesion-dependent signals during leukocyte migration and extravasation. Our findings also suggest an alternative mechanism, distinct from interference with Ras-proximal signaling, by which Rap1 might mediate transformation reversion.
Reedquist
K A
KA
Laboratory for Physiological Chemistry, Centre for Biomedical Genetics, Utrecht University Medical Center, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Ross
E
E
Koop
E A
EA
Wolthuis
R M
RM
Zwartkruis
F J
FJ
van Kooyk
Y
Y
Salmon
M
M
Buckley
C D
CD
Bos
J L
JL
D015703:Antigens, CD / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology*; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000737:chemistry / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D020827:rap1 GTP-Binding Proteins