<scp>l</scp>-Selectin activates the Ras pathway via the tyrosine kinase p56<sup>lck</sup>

Brenner, Birgit; Gulbins, E; Schlottmann, Klaus; Koppenhoefer, Ursula; Busch, Gillian L.; Walzog, Barbara; Steinhausen, M.; Coggeshall, K. Mark; Linderkamp, Otwin; Läng, Florian

doi:10.1073/pnas.93.26.15376

Cited by 134 publications

(119 citation statements)

References 45 publications

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“…T cell numbers declined with kinetics similar to those described previously following ablation of either MHC expression (9) or expression of the TCR itself (33). However, both Lck and Fyn have been implicated in the signaling of other cell surface molecules as diverse as CD28 (35), CD44 (36), L-selectin (37), and cytokine receptors (38,39). In principle, therefore, the requirement of Lck and Fyn for T cell survival may not be specifically for transducing TCR signals.…”

Section: Discussionmentioning

confidence: 54%

TCR Signals Mediated by Src Family Kinases Are Essential for the Survival of Naive T Cells

Seddon¹,

Zamoyska²

2002

The Journal of Immunology

109

101

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The role of TCR signals triggered by recognition of self MHCs in maintaining the survival of naive peripheral T cells remains controversial. Here we examine the role of the Src family kinases, p56lck (Lck) and p59fyn (Fyn), in the survival of naive T cells. We show that long term survival requires a combination of signals transduced by Src family kinases and signals through the IL-7R. In the absence of either one, naive T cells die slowly, but if both signals are removed, cell loss is greatly accelerated. The TCR signal can be mediated by either Fyn or Lck at wild-type levels of expression, but not by Lck alone if expressed suboptimally. The disappearance of T cells in the absence of Fyn and Lck was associated with a complete loss of TCRζ-chain phosphorylation and down-regulation of CD5, both of which are also MHC contact dependent, indicating that the Src family kinases are critical for transducing a TCR-MHC survival signal.

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Section: Discussionmentioning

confidence: 54%

TCR Signals Mediated by Src Family Kinases Are Essential for the Survival of Naive T Cells

Seddon¹,

Zamoyska²

2002

The Journal of Immunology

109

101

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“…Many reports have described L-selectin as a signaling receptor (47)(48)(49)(50)(51)(52)(53)(54). The mechanism by which L-selectin transduces signals is currently not known.…”

Section: Discussionmentioning

confidence: 99%

Mutagenesis of the Ezrin-Radixin-Moesin Binding Domain of L-selectin Tail Affects Shedding, Microvillar Positioning, and Leukocyte Tethering

Ivetič

Florey

Deka³

et al. 2004

Journal of Biological Chemistry

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L-selectin is a cell adhesion molecule that mediates the initial capture (tethering) and subsequent rolling of leukocytes along ligands expressed on endothelial cells. We have previously identified ezrin and moesin as novel binding partners of the 17-amino acid L-selectin tail, but the biological role of this interaction is not known. Here we identify two basic amino acid residues within the Lselectin tail that are required for binding to ezrin-radixinmoesin (ERM) proteins: arginine 357 and lysine 362. Lselectin mutants defective for ERM binding show reduced localization to microvilli and decreased phorbol 12-myristate 13-acetate-induced shedding of the L-selectin ectodomain. Cells expressing these L-selectin mutants have reduced tethering to the L-selectin ligand P-selectin glycoprotein ligand-1, but rolling velocity on P-selectin glycoprotein ligand-1 is not affected. These results suggest that ERM proteins are required for microvillar positioning of L-selectin and that this is important both for leukocyte tethering and L-selectin shedding.

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“…Lck for the activation of the Ras pathway (36). Moreover, a PSGL-1 mutant lacking the IC tail and thus missing a putative ERM binding domain still concentrates on microvilli of primary leukocytes (6).…”

Section: Discussionmentioning

confidence: 99%

The Transmembrane Domains of L-selectin and CD44 Regulate Receptor Cell Surface Positioning and Leukocyte Adhesion under Flow

Buscher

Riese

Shakibaei

et al. 2010

Journal of Biological Chemistry

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During inflammation and immune surveillance, initial contacts (tethering) between free-flowing leukocytes and the endothelium are vitally dependent on the presentation of the adhesion receptor L-selectin on leukocyte microvilli. Determinants that regulate receptor targeting to microvilli are, however, largely elusive. Therefore, we systematically swapped the extracellular (EC), transmembrane (TM), and intracellular (IC) domains of L-selectin and CD44, a hyaluronan receptor expressed on the cell body and excluded from microvilli. Electron microscopy of transfected human myeloid K562 cells showed that the highly conserved TM domains are responsible for surface positioning. The TM segment of L-selectin forced chimeric molecules to microvilli, and the CD44 TM domain evoked expression on the cell body, whereas the IC and EC domains hardly influenced surface localization. Transfectants with microvillus-based chimeras showed a significantly higher adhesion rate under flow but not under static conditions compared with cells with cell body-expressed receptors. Substitution of the IC domain of L-selectin caused diminished tethering but no change in surface distribution, indicating that both microvillus positioning and cytoskeletal anchoring contribute to leukocyte tethering. These findings demonstrate that TM domains of L-selectin and CD44 play a crucial role in cell adhesion under flow by targeting receptors to microvilli or the cell body, respectively.Neutrophil invasion at sites of inflammation as well as lymphocyte recirculation from blood into secondary lymphoid tissue require that free-flowing leukocytes become activated and subsequently exit the bloodstream. At the molecular level, the cells undergo a closely orchestrated cascade of interactions with the endothelium, each step consisting of a characteristic pattern of receptors, their ligands, cytokines, and chemoattractants (1, 2).Distinct cell surface receptor segregation is a widely observed phenomenon with effects on cell proliferation, migration, and tumorigenesis (3). Leukocyte membrane protrusions known as microvilli serve as active grouping sites for a variety of surface receptors including L-selectin (4), ␣4-integrins (5), P-selectin glycoprotein ligand 1 (PSGL-1) 3 (6, 7), CD4, and the chemokine receptors CCR5 and CXCR4 (8). In contrast, the hyaluronan receptor CD44 (4) and the integrins ␣M␤2 (Mac-1) and ␣L␤2 (LFA-1) (9, 10) show expression on the planar cell body excluding microvilli.Both L-selectin and CD44 are type I integral membrane glycoproteins expressed on most circulating leukocytes. L-selectin knock-out mice show a profound defect of lymphocyte accumulation in secondary lymphatic tissue and of neutrophils at sites of inflammation (11). CD44 is involved in many physiological processes, including lymphocyte activation, adhesion, and proliferation (12). There is also increasing evidence that CD44 and L-selectin contribute to tumor metastasis (13,14).Under many physiologic conditions, L-selectin initiates the first step of the adhesion cascade (15,1...

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l-Selectin activates the Ras pathway via the tyrosine kinase p56^lck

Abstract: ABSTRACT

Cited by 134 publications

References 45 publications

TCR Signals Mediated by Src Family Kinases Are Essential for the Survival of Naive T Cells

TCR Signals Mediated by Src Family Kinases Are Essential for the Survival of Naive T Cells

Mutagenesis of the Ezrin-Radixin-Moesin Binding Domain of L-selectin Tail Affects Shedding, Microvillar Positioning, and Leukocyte Tethering

The Transmembrane Domains of L-selectin and CD44 Regulate Receptor Cell Surface Positioning and Leukocyte Adhesion under Flow

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l-Selectin activates the Ras pathway via the tyrosine kinase p56lck

Abstract: ABSTRACT

Cited by 134 publications

References 45 publications

TCR Signals Mediated by Src Family Kinases Are Essential for the Survival of Naive T Cells

TCR Signals Mediated by Src Family Kinases Are Essential for the Survival of Naive T Cells

Mutagenesis of the Ezrin-Radixin-Moesin Binding Domain of L-selectin Tail Affects Shedding, Microvillar Positioning, and Leukocyte Tethering

The Transmembrane Domains of L-selectin and CD44 Regulate Receptor Cell Surface Positioning and Leukocyte Adhesion under Flow

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l-Selectin activates the Ras pathway via the tyrosine kinase p56^lck