Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

Palacios, Emil H.; Weiss, Arthur

doi:10.1038/sj.onc.1208074

Cited by 637 publications

(607 citation statements)

References 104 publications

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“…Moreover, we also detected a TCR-triggered increase in phosphorylation of NTB-A-associated LCK on tyrosine 394 (Y394) (Fig. 1C), which is indicative of an active conformation (12). In fact, an additional higher m.w.…”

Section: Ricd Of Human T Cells Is Not Dependent On Fynmentioning

confidence: 72%

“…However, the mechanism by which NTB-A and SAP enhance TCR signaling during restimulation is still unclear. Two Srcfamily kinases are primarily involved in initiating TCR signaling: LCK and FYN (12). FYN is the major Src-family kinase shown to mediate signal transduction of SLAM-Rs (including NTB-A) in thymocytes and NK cells (13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Ricd Of Human T Cells Is Not Dependent On Fynmentioning

confidence: 99%

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SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

Katz

Krummey

Larsen

et al. 2014

The Journal of Immunology

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Upon TCR restimulation, activated, cycling T cells can undergo a self-regulatory form of apoptosis known as restimulation-induced cell death (RICD). We previously demonstrated that RICD is impaired in T cells from patients with X-linked lymphoproliferative disease, which lack SLAM-associated protein (SAP) expression. Both SAP and the specific SLAM receptor NK, T, and B cell Ag (NTB-A) are required for RICD, but the mechanism by which these molecules promote a strong, proapoptotic signal through the TCR remains unclear. In this article, we show that the Src-family kinase LCK, but not FYN, associates with NTB-A in activated human T cells. This association increased after TCR restimulation in a SAP-dependent manner, requiring both immunoreceptor tyrosine-based switch motifs in the NTB-A cytoplasmic tail. Both NTB-A–associated LCK phosphorylation and kinase activity were enhanced in restimulated T cells, amplifying proximal TCR signaling. In contrast, TCR-induced LCK association with NTB-A, as well as phosphorylation and kinase activity, was reduced in T cells from patients with X-linked lymphoproliferative disease or normal T cells transfected with SAP-specific small interfering RNA, consistent with RICD resistance. Collectively, our data reveal how SAP nucleates a previously unknown signaling complex involving NTB-A and LCK to potentiate RICD of activated human T cells.

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Section: Ricd Of Human T Cells Is Not Dependent On Fynmentioning

confidence: 72%

Section: Ricd Of Human T Cells Is Not Dependent On Fynmentioning

confidence: 99%

SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

Katz

Krummey

Larsen

et al. 2014

The Journal of Immunology

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“…signaling platforms [40,41]. This compartmentalization of CD44-CD49d complexes could be important for LNC adhesion, migration and activation.…”

Section: Membrane Subdomain Localization Of the Cd44-cd49d Complexmentioning

confidence: 98%

In vivo CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

2006

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CD44 is involved in leukocyte migration and activation and has recently been reported to contribute to leukocyte extravasation by associating with CD49d. We explored whether similar changes in CD44 activity are seen in vivo using murine alopecia areata (AA) as a chronic, organ‐related autoimmune disease model system. Expression of the activated, hyaluronan‐binding form of CD44, and of CD49d, was elevated in draining lymph node cells (LNC) of AA‐affected mice as compared to control mice. LNC of AA mice displayed increased motility, proliferative activity and apoptosis resistance, which were equally well inhibited by anti‐CD44 and anti‐CD49d. The latter is the sequelae of the association between CD44 and CD49d that is seen in activated lymphocytes. Significantly, due to CD44‐CD49d complex formation, CD44 gains access to focal adhesion kinase and CD49d gains access to CD44‐associated lck and ezrin, such that downstream kinases become activated via CD44 or CD49d engagement. Thus, by their association, CD44 and CD49d mutually avail themselves of the partner's signaling pathways and the ligand binding of each one triggers signaling pathways of both. This strongly influences the lymphocytes’ activation state and function.

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“…26 Lymphoid protein tyrosine phosphatase is expressed in T lymphocytes and associates with C-terminal Src kinase (CSK) to form a complex that suppresses the T-cell receptor signalling kinases LCK and FYN. [27][28] Experimental evidence suggests that the disease-associated LYP variant Trp620 prevents the interaction of LYP with CSK. 18 Consequently, the T-cell receptor-associated kinases might be able to induce T-cell activation in an uncontrolled manner and this may increase the overall reactivity of the immune system and predispose an individual to autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

et al. 2005

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Vitiligo is an acquired hypomelanotic skin disorder resulting from the loss of functional melanocytes from the cutaneous epidermis and autoimmunity has been suggested to play a part in its pathogenesis. Recently, the missense R620W polymorphism in the PTPN22 gene, which encodes lymphoid protein tyrosine phosphatase (LYP), has been associated with susceptibility to autoimmune disorders. The objective of this study was to ascertain if the disease-associated 1858T allele was also associated with generalised (nonsegmental) vitiligo and so the frequencies of the PTPN22 1858C/T alleles were investigated in 165 English patients with generalised vitiligo and 304 ethnically matched control subjects. The results indicated that the 1858T allele was significantly over-represented in the vitiligo patient group compared with the control cohort. Of 330 vitiligo alleles, 48 (14.5%) encoded the Trp620 variant compared to 52 of 608 (8.6%) control alleles (P ¼ 0.006; odds ratio ¼ 1.82, 95% confidence interval ¼ 1.17-2.82). The results indicate that the LYP missense R620W polymorphism may have an influence on the development of generalised vitiligo and provide further evidence for autoimmunity as an aetiological factor with respect to this disease.

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Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation

Cited by 637 publications

References 104 publications

SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

In vivo CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

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