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1.
Sci Rep ; 11(1): 16951, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417497

RESUMO

T-cell activation and cellular expansion by common gamma chain cytokines such as Interleukin-2 is necessary for adaptive immunity. However, when unregulated these same pathways promote pathologies ranging from autoimmune disorders to cancer. While the functional role of Interleukin-2 and downstream effector molecules is relatively clear, the repertoire of phosphoregulatory proteins downstream of this pathway is incomplete. To identify phosphoproteins downstream of common gamma chain receptor, YT cells were radiolabeled with [32P]-orthophosphate and stimulated with Interleukin-2. Subsequently, tyrosine phosphorylated proteins were immunopurified and subjected to tandem mass spectrometry-leading to the identification of CrkL. Phosphoamino acid analysis revealed concurrent serine phosphorylation of CrkL and was later identified as S114 by mass spectrometry analysis. S114 was inducible through stimulation with Interleukin-2 or T-cell receptor stimulation. Polyclonal antibodies were generated against CrkL phospho-S114, and used to show its inducibility by multiple stimuli. These findings confirm CrkL as an Interleukin-2 responsive protein that becomes phosphorylated at S114 by a kinase/s downstream of PI3K and MEK/ERK signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Citocinas/metabolismo , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Interleucina-2/metabolismo , Fosfosserina/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Anticorpos/metabolismo , Linhagem Celular , Humanos , Sistema de Sinalização das MAP Quinases , Peptídeos/química , Peptídeos/metabolismo , Fosforilação , Fosfotirosina/metabolismo , Processamento de Proteína Pós-Traducional , Serina-Treonina Quinases TOR/metabolismo
2.
Biochem J ; 475(18): 2907-2923, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30120106

RESUMO

Regulation of intracellular signaling pathways in lymphocytes is critical for cell homeostasis and immune response. Interleukin-2 (IL-2), a key regulator of lymphocytes, signals following receptor-ligand engagement and subsequent recruitment and activation of effector proteins including JAKs and STATs. Lymphocytes can also be regulated by the central nervous system through the ß2 adrenergic receptor (ß2AR) pathway which can affect cell trafficking, proliferation, differentiation, and cytokine production. The cross-talk between these two signaling pathways represents an important mechanism that has yet to be fully elucidated. The present study provides evidence for communication between the IL-2 receptor (IL-2R) and ß2AR. Treatment of human lymphoid cell lines with the ß2AR agonist isoproterenol (ISO) alone increased cAMP levels and mediated a stimulatory response by activating AKT and ERK to promote cell viability. Interestingly, ISO activation of ß2AR also induced threonine phosphorylation of the IL-2Rß. In contrast, ISO treatment prior to IL-2 stimulation produced an inhibitory signal that disrupted IL-2 induced activation of the JAK/STAT, MEK/ERK, and PI3K pathways by inhibiting the formation of the IL-2R beta-gamma chain complex, and subsequently cell proliferation. Moreover, γc-family cytokines-mediated STAT5 activation was also inhibited by ISO. These results suggest a molecular mechanism by which ß2AR signaling can both stimulate and suppress lymphocyte responses and thus explain how certain therapeutic agents, such as vasodilators, may impact immune responsiveness.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Interleucina-2/metabolismo , Isoproterenol/farmacologia , Linfócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Subunidade beta de Receptor de Interleucina-2/metabolismo , Linfócitos/citologia , Fator de Transcrição STAT5/metabolismo
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