The small GTPase, Rap1, mediates CD31-induced integrin adhesion

K A Reedquist, E Ross, E A Koop, R M Wolthuis, F J Zwartkruis, Y van Kooyk, M Salmon, C D Buckley, J L Bos

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1151-8
Number of pages8
JournalJournal of Cell Biology
Volume148
Issue number6
Publication statusPublished - 20 Mar 2000

Cite this

Reedquist, K. A., Ross, E., Koop, E. A., Wolthuis, R. M., Zwartkruis, F. J., van Kooyk, Y., ... Bos, J. L. (2000). The small GTPase, Rap1, mediates CD31-induced integrin adhesion. Journal of Cell Biology, 148(6), 1151-8.
Reedquist, K A ; Ross, E ; Koop, E A ; Wolthuis, R M ; Zwartkruis, F J ; van Kooyk, Y ; Salmon, M ; Buckley, C D ; Bos, J L. / The small GTPase, Rap1, mediates CD31-induced integrin adhesion. In: Journal of Cell Biology. 2000 ; Vol. 148, No. 6. pp. 1151-8.
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abstract = "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.",
keywords = "Antigens, CD/physiology, Cell Adhesion/physiology, Cell Adhesion Molecules/metabolism, Humans, Integrin alpha4beta1, Integrins/physiology, Jurkat Cells, Lymphocyte Function-Associated Antigen-1/physiology, Platelet Endothelial Cell Adhesion Molecule-1/chemistry, Receptors, Lymphocyte Homing/physiology, Recombinant Fusion Proteins/metabolism, Signal Transduction, T-Lymphocytes/physiology, Transfection, Vascular Cell Adhesion Molecule-1/metabolism, rap1 GTP-Binding Proteins/metabolism",
author = "Reedquist, {K A} and E Ross and Koop, {E A} and Wolthuis, {R M} and Zwartkruis, {F J} and {van Kooyk}, Y and M Salmon and Buckley, {C D} and Bos, {J L}",
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Reedquist, KA, Ross, E, Koop, EA, Wolthuis, RM, Zwartkruis, FJ, van Kooyk, Y, Salmon, M, Buckley, CD & Bos, JL 2000, 'The small GTPase, Rap1, mediates CD31-induced integrin adhesion' Journal of Cell Biology, vol. 148, no. 6, pp. 1151-8.

The small GTPase, Rap1, mediates CD31-induced integrin adhesion. / Reedquist, K A; Ross, E; Koop, E A; Wolthuis, R M; Zwartkruis, F J; van Kooyk, Y; Salmon, M; Buckley, C D; Bos, J L.

In: Journal of Cell Biology, Vol. 148, No. 6, 20.03.2000, p. 1151-8.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The small GTPase, Rap1, mediates CD31-induced integrin adhesion

AU - Reedquist, K A

AU - Ross, E

AU - Koop, E A

AU - Wolthuis, R M

AU - Zwartkruis, F J

AU - van Kooyk, Y

AU - Salmon, M

AU - Buckley, C D

AU - Bos, J L

PY - 2000/3/20

Y1 - 2000/3/20

N2 - 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.

AB - 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.

KW - Antigens, CD/physiology

KW - Cell Adhesion/physiology

KW - Cell Adhesion Molecules/metabolism

KW - Humans

KW - Integrin alpha4beta1

KW - Integrins/physiology

KW - Jurkat Cells

KW - Lymphocyte Function-Associated Antigen-1/physiology

KW - Platelet Endothelial Cell Adhesion Molecule-1/chemistry

KW - Receptors, Lymphocyte Homing/physiology

KW - Recombinant Fusion Proteins/metabolism

KW - Signal Transduction

KW - T-Lymphocytes/physiology

KW - Transfection

KW - Vascular Cell Adhesion Molecule-1/metabolism

KW - rap1 GTP-Binding Proteins/metabolism

M3 - Article

VL - 148

SP - 1151

EP - 1158

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 6

ER -

Reedquist KA, Ross E, Koop EA, Wolthuis RM, Zwartkruis FJ, van Kooyk Y et al. The small GTPase, Rap1, mediates CD31-induced integrin adhesion. Journal of Cell Biology. 2000 Mar 20;148(6):1151-8.