Activation of T Cells by Cross‐Linking Qa‐2, the <i>Ped</i> Gene Product, Requires Fyn

Fazio, S. R. De; Warner, Carol M.

doi:10.1111/j.1600-0897.2007.00503.x

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…Also, both sDab1 isoforms and sFyn-B were expressed in adipose tissue, and it was shown that the loss of Fyn markedly improved insulin sensitivity[ 34 ], hence, they might interact to influence fatty acid metabolism. The high expression level of sFyn-T in spleen and lung suggests a role in the immune system, as shown in other species; for instance, Fyn is required for the activation of T cells[ 35 ]. Further investigation is needed to explore the multiple roles of sDab1 isoforms in various tissues in addition to the regulation of neuronal migration and neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

Identification of alternatively spliced Dab1 and Fyn isoforms in pig

et al. 2011

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BackgroundDisabled-1 (Dab1) is an adaptor protein that is essential for the intracellular transduction of Reelin signaling, which regulates the migration and differentiation of postmitotic neurons during brain development in vertebrates. Dab1 function depends on its tyrosine phosphorylation by Src family kinases, especially Fyn.ResultsWe have isolated alternatively spliced forms of porcine Dab1 from brain (sDab1) and liver (sDab1-Li) and Fyn from brain (sFyn-B) and spleen (sFyn-T). Radiation hybrid mapping localized porcine Dab1 (sDab1) and Fyn (sFyn) to chromosomes 6q31-35 and 1p13, respectively. Real-time quantitative RT-PCR (qRT-PCR) demonstrated that different isoforms of Dab1 and Fyn have tissue-specific expression patterns, and sDab1 and sFyn-B display similar temporal expression characteristics in the developing porcine cerebral cortex and cerebellum. Both sDab1 isoforms function as nucleocytoplasmic shuttling proteins. It was further shown that sFyn phosphorylates sDab1 at tyrosyl residues (Tyr) 185, 198/200 and 232, whereas sDab1-Li was phosphorylated at Tyr 185 and Tyr 197 (corresponding to Y232 in sDab1) in vitro.ConclusionsAlternative splicing generates natural sDab1-Li that only carries Y185 and Y197 (corresponding to Y232 in sDab1) sites, which can be phosphorylated by Fyn in vitro. sDab1-Li is an isoform that is highly expressed in peripheral organs. Both isoforms are suggested to be nucleocytoplasmic shuttling proteins. Our results imply that the short splice form sDab1-Li might regulate cellular responses to different cell signals by acting as a dominant negative form against the full length sDab1 variant and that both isoforms might serve different signaling functions in different tissues.

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Section: Discussionmentioning

confidence: 99%

Identification of alternatively spliced Dab1 and Fyn isoforms in pig

et al. 2011

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“…Since the Src family kinases (SFKs) has been involved in EMT 28 , 29 and pluripotency 30 , and Qa-2 appears to mediate activation of the SFK member Fyn 31 , we treated 4T1m and 4T1t cell lines with two well-established inhibitors of SFK activity: Dasatinib and PP2 32 . Dasatinib at a concentration of 100 nM had an apparent cytotoxic effect on the cultures, causing a high proportion of cell death in both cell lines.…”

Section: Resultsmentioning

confidence: 99%

Reduced expression of the murine HLA-G homolog Qa-2 is associated with malignancy, epithelial-mesenchymal transition and stemness in breast cancer cells

Silva

Martín-Villar

Martı́n-Pérez

et al. 2017

Sci Rep

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Qa-2 is believed to mediate a protective immune response against cancer; however, little is known about the role of Qa-2 in tumorigenesis. Here, we used 4T1 breast cancer cells to study the involvement of Qa-2 in tumor progression in a syngeneic host. Qa-2 expression was reduced during in vivo tumor growth and in cell lines derived from 4T1-induced tumors. Tumor-derived cells elicited an epithelial-mesenchymal transition associated with upregulation of Zeb1 and Twist1/2 and enhanced tumor initiating and invasive capacities. Furthermore, these cells showed increased stem characteristics, as demonstrated by upregulation of Hes1, Sox2 and Oct3/4, and enrichment of CD44high/CD24median/low cells. Remarkably, Qa-2 cell-surface expression was excluded from the CD44high/CD24median/low subpopulation. Tumor-derived cells showed increased Src activity, and treatment of these cells with the Src kinase inhibitor PP2 enhanced Qa-2 but reduced Sox2 and CD44high/CD24median/low expression levels, suggesting that Src signaling, while positively associated with stemness, negatively regulates Qa-2 expression in breast cancer. Finally, overexpression of the Qa-2 family member Q7 on the cell surface slowed down in vivo tumor growth and reduced the metastatic potential of 4T1 cells. These results suggest an anti-malignant role for Qa-2 in breast cancer development, which appears to be absent from cancer stem cells.

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“…However, the α3 domain of Qa-2 is unable to interact with CD8 in order to effectively activate cytotoxic T cells (44). Qa-2 has been reported to mediate signal transduction pathways, as antibody-induced crosslinking of Qa-2 promoted proliferation of resting T cells depending on Fyn (a member of the Src family of kinases), PI-3 kinase and Akt (45). Also, Qa-2 is required for the selection of intraepithelial unconventional CD8αα/TCRαβ T cells, which appear to be regulatory cells involved in maintaining intestinal integrity (46).…”

Section: The Murine Non-classical Mhc Complex Qa-2 Its Role In Embrymentioning

confidence: 99%

New Insights Into the Role of Qa-2 and HLA-G Non-classical MHC-I Complexes in Malignancy

2018

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It is well established that the immune system can identify and destroy neoplastic transformed cells in a process known as immunosurveillance. Most studies have focused on the classical major histocompatibility complex (MHC) class Ia molecules, which are known to play an important role on the presentation of tumor antigens to the immune system in order to activate a response against tumor cells. However, a larger family of non-classical MHC class Ib-related molecules has received less attention. In this mini-review, we discuss the role of class Ib murine Qa-2 and its proposed human HLA-G homolog on immunosurveillance during embryogenesis and cancer. Whereas, both HLA-G and Qa-2 are involved in immune tolerance in pregnancy, the current evidence suggests that they play opposite roles in cancer. HLA-G appears to promote tumor progression while Qa-2 acts as a tumor suppressor awaking the immune system to reject tumor cells, as suggested by studies on different cancer cell models, such as melanoma, lymphoma, lung carcinoma, and our own results in mammary carcinoma.

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Activation of T Cells by Cross‐Linking Qa‐2, the Ped Gene Product, Requires Fyn

Abstract: Fyn, PI-3 kinase, and Akt are required for the activation of T cells by cross-linking Qa-2.

Cited by 7 publications

References 48 publications

Identification of alternatively spliced Dab1 and Fyn isoforms in pig

Identification of alternatively spliced Dab1 and Fyn isoforms in pig

Reduced expression of the murine HLA-G homolog Qa-2 is associated with malignancy, epithelial-mesenchymal transition and stemness in breast cancer cells

New Insights Into the Role of Qa-2 and HLA-G Non-classical MHC-I Complexes in Malignancy

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