Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation.

Kanner, Steven B.; Grosmaire, Laura S.; Ledbetter, Jeffrey A.; Damle, Nitin K.

doi:10.1073/pnas.90.15.7099

Cited by 173 publications

(117 citation statements)

References 56 publications

(43 reference statements)

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“…It thus seems reasonable to assume that they exert the same function in the context of a T cell/APC interaction. Possible mediators of CD28 and LFA-1 signal transduction are phosphatidylinositol 3-kinase (44,45) and phospholipase C␥ (46).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

Tskvitaria-Fuller

Rozelle²,

Yin³

et al. 2003

The Journal of Immunology

112

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The localization of receptors, signaling intermediates, and cytoskeletal components at the T cell/APC interface is thought to be a major determinant of efficient T cell activation. However, important questions remain open. What are the dynamics of the T cell cytoskeleton as a potential mediator of such localization? How are they regulated by the TCR and costimulatory receptors? Do they actually mediate receptor localization? In this study, we have addressed these questions. Even under limiting T cell activation conditions, actin accumulated immediately and transiently at the T cell/APC interface, the microtubule organizing center reoriented toward it. In contrast, sustained (>5 min) actin accumulation in highly dynamic patterns depended on an optimal T cell stimulus: high concentrations of the strong TCR ligand agonist peptide/MHC and engagement of the costimulatory receptors CD28 and LFA-1 were required in an overlapping, yet distinct, fashion. Intact sustained actin dynamics were required for interface accumulation of TCR/MHC in a central pattern and for efficient T cell proliferation, as established using a novel approach to selectively block only the sustained actin dynamics. These data suggest that control of specific elements of actin dynamics by TCR and costimulatory receptors is a mechanism to regulate the efficiency of T cell activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

Tskvitaria-Fuller

Rozelle²,

Yin³

et al. 2003

The Journal of Immunology

112

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“…The cross-linking of ␤ 2 integrins on T cells leads to augmentation of T cell receptor-induced PLC␥ stimulation and to Ca 2ϩ mobilization (28). The inhibition of PLC␥ blocks integrin-mediated collagen lattice contraction by dermal fibroblasts (29).…”

Section: Discussionmentioning

confidence: 99%

Phospholipase Cγ Binds α1β1Integrin and Modulates α1β1 Integrin-specific Adhesion

Vossmeyer

Hofmann

Löster

et al. 2002

Journal of Biological Chemistry

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Integrin adhesion receptors have been implicated in bidirectional signal transduction. The dynamic regulation of integrin affinity and avidity as well as post-ligand effects involved in outside-in signaling depends on the interaction of integrins with cytoskeletal and signaling proteins. In this study, we attempted to identify cytoplasmic binding partners of ␣ 1 ␤ 1 integrin. We were able to show that cell adhesion to ␣ 1 ␤ 1 -specific substrates results in the association of phospholipase C␥ (PLC␥) with the ␣ 1 ␤ 1 integrin independent of PLC␥ tyrosine phosphorylation. Using peptide-binding assays, the membrane proximal sequences within the ␣ 1 ␤ 1 integrin subunits were identified as binding sites for PLC␥. In particular, the conserved sequence of ␤ 1 subunit binds the enzyme very efficiently. Because purified PLC␥ also binds the integrin peptides, binding seems to be direct. Inhibition of PLC by U73122 leads to reduced cell adhesion on ␣ 1 ␤ 1 -specific substrates. Cells lacking the conserved domain of the ␣ 1 subunit fail to respond to the PLC inhibition, indicating that this domain is necessary for PLC-dependent adhesion modulation of ␣ 1 ␤ 1 integrin.

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“…For integrin LFA-1 in particular, the intracellular signals that are generated in T cells following ligand engagement of this receptor have not been fully characterized. It has been described that LFA-1 signaling includes phosphorylation of phos-pholipase C␥1, phospholipid hydrolysis, activation of different isoenzymes of protein kinase C, mobilization of intracellular Ca 2ϩ , and activation of tyrosine kinases (12)(13)(14)(15)(16)(17)(18). We have reported recently that activation of integrin LFA-1 on T lymphocytes and subsequent cell adhesion onto immobilized ligand ICAM-1 leads to a T cell phenotype characterized by strong adhesion, acquisition of an elongated morphology, cessation of cell motility, and activation of the intracellular tyrosine kinase PYK-2 (17)(18)(19).…”

mentioning

confidence: 99%

Signaling through the Leukocyte Integrin LFA-1 in T Cells Induces a Transient Activation of Rac-1 That Is Regulated by Vav and PI3K/Akt-1

Sánchez-Martı́n

Sánchez-Sánchez

Gutiérrez-López

et al. 2004

Journal of Biological Chemistry

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Integrin LFA-1 is a receptor that is able to transmit multiple intracellular signals in leukocytes. Herein we show that LFA-1 induces a potent and transient increase in the activity of the small GTPase Rac-1 in T cells. Maximal Rac-1 activity peaked 10 -15 min after LFA-1 stimulation and rapidly declined to basal levels at longer times. We have identified Vav, a guanine nucleotide exchange factor for Rac-1, and PI3K/Akt, as regulators of the activation and inactivation phases of the activity of Rac-1, respectively, in the context of LFA-1 signaling based on the following experimental evidence: (i) LFA-1 induced activation of Vav and PI3K/Akt with kinetics consistent with a regulatory role for these molecules on Rac-1, (ii) overexpression of a constitutively active Vav mutant induces activation of Rac independently of LFA-1 stimulation whereas overexpression of a dominant-negative Vav mutant blocks LFA-1-mediated Rac activation, (iii) pharmacological inhibition of PI3K/Akt prevented the fall in the activity of Rac-1 after its initial activation but had no effect on Vav activity, and (iv) overexpression of a dominant-negative or a constitutively active Akt-1 induced or inhibited, respectively, Rac-1 activity. Finally, we show that T cells with a sustained Rac activity have impaired capacity to elongate onto ICAM-1. These results demonstrate that down-regulation of the activity of this GTPase is a requirement for the regulation of T cell morphology and motility and highlight the importance of temporal regulation of the signaling triggered from this integrin.

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Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation.

Cited by 173 publications

References 56 publications

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

Phospholipase Cγ Binds α1β1Integrin and Modulates α1β1 Integrin-specific Adhesion

Signaling through the Leukocyte Integrin LFA-1 in T Cells Induces a Transient Activation of Rac-1 That Is Regulated by Vav and PI3K/Akt-1

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