p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells

Patrussi, Laura; Ulivieri, Cristina; Lucherini, Orso Maria; Paccani, Silvia Rossi; Gamberucci, Alessandra; Lanfrancone, Luisa; Pelicci, Pier Giuseppe; Baldari, Cosima T.

doi:10.1182/blood-2007-01-068411

Cited by 55 publications

(81 citation statements)

References 47 publications

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“…In this regard, it has recently been shown that the cytosolic adapter protein Shc is phosphorylated upon CXCR4 stimulation and assembles into a complex that includes Lck, ZAP70, Vav1, and LAT (59). Moreover, Shc-deficient Jurkat T cells show an attenuated migratory capacity and impaired F-actin dynamics upon CXCR4 stimulation, and mutation of critical tyrosine residues of Shc (YY 238/240 or Y 317 ) results in defective phosphorylation of Vav1 and Itk (59).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Shc-deficient Jurkat T cells show an attenuated migratory capacity and impaired F-actin dynamics upon CXCR4 stimulation, and mutation of critical tyrosine residues of Shc (YY 238/240 or Y 317 ) results in defective phosphorylation of Vav1 and Itk (59). Thus, Shc might be an attractive candidate to connect CXCR4 with the Vav1-Itk-dependent pathway of F-actin polymerization and T cell migration (59). It will be important to assess the role of Shc in CXCR4-induced inside-out signaling, adhesion, and Rap1 activation in future studies.…”

Section: Discussionmentioning

confidence: 99%

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Src Homology 2-Domain Containing Leukocyte-Specific Phosphoprotein of 76 kDa Is Mandatory for TCR-Mediated Inside-Out Signaling, but Dispensable for CXCR4-Mediated LFA-1 Activation, Adhesion, and Migration of T Cells

Horn

Wang

Reichardt

et al. 2009

The Journal of Immunology

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Engagement of the TCR or of chemokine receptors such as CXCR4 induces adhesion and migration of T cells via so-called inside-out signaling pathways. The molecular processes underlying inside-out signaling events are as yet not completely understood. In this study, we show that TCR- and CXCR4-mediated activation of integrins critically depends on the membrane recruitment of the adhesion- and degranulation-promoting adapter protein (ADAP)/Src kinase-associated phosphoprotein of 55 kDa (SKAP55)/Rap1-interacting adapter protein (RIAM)/Rap1 module. We further demonstrate that the Src homology 2 domain containing leukocyte-specific phosphoprotein of 76 kDa (SLP76) is crucial for TCR-mediated inside-out signaling and T cell/APC interaction. Besides facilitating membrane recruitment of ADAP, SKAP55, and RIAM, SLP76 regulates TCR-mediated inside-out signaling by controlling the activation of Rap1 as well as Rac-mediated actin polymerization. Surprisingly, however, SLP76 is not mandatory for CXCR4-mediated inside-out signaling. Indeed, both CXCR4-induced T cell adhesion and migration are not affected by loss of SLP76. Moreover, after CXCR4 stimulation, the ADAP/SKAP55/RIAM/Rap1 module is recruited to the plasma membrane independently of SLP76. Collectively, our data indicate a differential requirement for SLP76 in TCR- vs CXCR4-mediated inside-out signaling pathways regulating T cell adhesion and migration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Src Homology 2-Domain Containing Leukocyte-Specific Phosphoprotein of 76 kDa Is Mandatory for TCR-Mediated Inside-Out Signaling, but Dispensable for CXCR4-Mediated LFA-1 Activation, Adhesion, and Migration of T Cells

Horn

Wang

Reichardt

et al. 2009

The Journal of Immunology

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“…Intracellular Ca 2+ concentrations were determined in cells loaded with 3 mM Fura-2 (Molecular Probes) in 140 mM NaCl, 5.4 mM KCl, 1 mM MgCl 2 , 0.2 mM EGTA, and 15 mM HEPES (pH 7.4) in the presence of 1 mM Ca 2+ , as described (26). Loaded cells were sensitized with anti-DNP IgE (1 mg/ml) on ice for 1 h and stimulated with DNP-ALB (1 mg/ml or 20 ng/ml), thapsigargin (2 mM), or ATP (3 mM).…”

Section: Flow Cytometry and Ca 2+ Flux Analysismentioning

confidence: 99%

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

Ulivieri

Fanigliulo

Masi

et al. 2011

The Journal of Immunology

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Aggregation of FcεRI on mast cells activates signaling pathways, resulting in degranulation and cytokine release. Release of mast cell-derived inflammatory mediators is tightly regulated by the interplay of positive and negative signals largely orchestrated by adapter proteins. Among these, the Shc family adapter p52Shc, which couples immunoreceptors to Ras activation, positively regulates FcεRI-dependent signaling. Conversely, p66Shc was shown to uncouple the TCR for the Ras–MAPK pathway and prime T cells to undergo apoptotic death. Loss of p66Shc in mice results in breaking of immunologic tolerance and development of lupus-like autoimmune disease, which includes alopecia among its pathological manifestations. The presence of numerous activated mast cells in alopecic skin areas suggests a role for this adapter in mast cells. In this study, we addressed the involvement of p66Shc in FcεRI-dependent mast cell activation. We showed that p66Shc is expressed in mast cells and that mast cells from p66Shc−/− mice exhibit enhanced responses following Ag stimulation of FcεRI. Furthermore, using RBL-2H3 cell transfectants, we showed that aggregation of FcεRI resulted in the recruitment of a p66Shc–SHIP1 complex to linker for activation of T cells. Collectively, our data identified p66Shc as a negative regulator of mast cell activation.

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“…Following the in vitro treatment, 1 Â 10 6 live cells/sample (as determined by trypan blue exclusion) were loaded in Transwell filters (Costar, Corning, 5 mm pores) which were placed in 24-well plates containing medium without additives or with 100 ng/mL SDF-1a as described [45] as well as drugs. Loading control samples were set up by plating 1 Â 10 6 live cells, treated as above, in 24-well plates containing RPMI supplemented with 0.5% serum and drugs.…”

Section: Transwell Migration Assaysmentioning

confidence: 99%

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

et al. 2008

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Statins block the activity of HMG-CoA reductase, which catalyses the production of mevalonate, an intermediate in cholesterol biosynthesis, which is also a precursor of isoprenoids. In addition to lowering circulating cholesterol, these drugs display antiinflammatory and immunomodulatory activities in vitro; however, their effects on the development of adaptive immune responses in vivo, as well as the underlying mechanisms, are as yet largely unknown. Here we investigated the outcome of simvastatin treatment on a number of processes, which together orchestrate adaptive immunity to specific antigen. Simvastatin treatment resulted in a marked reduction of T and B cells in spleen, lymph nodes and peripheral blood in mice. This effect could be ascribed principally to an impairment of lymphocyte homing to secondary lymphoid organs. In addition, simvastatin was found to strongly inhibit T-cell responses to the MHCI restricted hen ovalbumin peptide antigen SIINFEKL and to impair ovalbumin uptake and cross-presentation by MHCI. Simvastatin also suppressed antibody responses to immunization with ovalbumin and delayed-type hypersensitivity to allergens. These activities could be largely accounted for by the simvastatin-dependent inhibition of HMG-CoA reductase. The data provide novel mechanistic insight into the activities of simvastatin in the highly complex context of the immune response.Key words: Apoptosis . Homing . Immune responses . Simvastatin IntroductionStatins are competitive inhibitors of HMG-CoA reductase, a major rate-limiting enzyme that controls HMG-CoA conversion to mevalonic acid in the cholesterol biosynthetic pathway. In addition to lowering circulating cholesterol, statins act as antiinflammatory and immunomodulatory agents [1]. These activities have been largely ascribed to their capacity to block isoprenoid production, and thereby to inhibit prenylation of small Ras superfamily GTPases, which are master regulators of cell activation and proliferation, cytoskeletal remodelling and membrane trafficking [2].Statins suppress T-cell activation both directly and by interfering with APC maturation and function. Statins inhibit T-cell activation, cell cycle progression and proliferation, as well as migration, both through an HMG-CoA-reductase-independent mechanism, involving allosteric inhibition of LFA-1 [3] and HMGCoA-reductase-dependent mechanisms, which rely on their capacity to inhibit prenylation of small GTPases [4,5]. Moreover, recent reports have provided evidence that some statins also 2832affect helper T-cell differentiation by promoting Th2 polarization and suppressing Th1 polarization both in vitro and in vivo [6,7]. This activity highlights statins as potential drugs in the treatment of diseases dominated by Th1 responses. Statins have been indeed shown to prevent or reverse several Th1-mediated autoimmune conditions in mice, such as autoimmune encephalomyelitis [8], spontaneous systemic lupus erythematosus [9,10], autoimmune myocarditis [11] and autoimmune retinal disease [12] via suppressio...

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p52Shc is required for CXCR4-dependent signaling and chemotaxis in T cells

Cited by 55 publications

References 47 publications

Src Homology 2-Domain Containing Leukocyte-Specific Phosphoprotein of 76 kDa Is Mandatory for TCR-Mediated Inside-Out Signaling, but Dispensable for CXCR4-Mediated LFA-1 Activation, Adhesion, and Migration of T Cells

Src Homology 2-Domain Containing Leukocyte-Specific Phosphoprotein of 76 kDa Is Mandatory for TCR-Mediated Inside-Out Signaling, but Dispensable for CXCR4-Mediated LFA-1 Activation, Adhesion, and Migration of T Cells

p66Shc Is a Negative Regulator of FcεRI-Dependent Signaling in Mast Cells

Simvastatin impairs humoral and cell‐mediated immunity in mice by inhibiting lymphocyte homing, T‐cell activation and antigen cross‐presentation

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