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首页> 外文期刊>Molecular and Cellular Biology >ADAP Regulates Cell Cycle Progression of T Cells via Control of Cyclin E and Cdk2 Expression through Two Distinct CARMA1-Dependent Signaling Pathways
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ADAP Regulates Cell Cycle Progression of T Cells via Control of Cyclin E and Cdk2 Expression through Two Distinct CARMA1-Dependent Signaling Pathways

机译：ADAP通过两个不同的CARMA1依赖信号通路，通过控制细胞周期蛋白E和Cdk2的表达来调节T细胞的细胞周期进程。

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Adhesion and degranulation-promoting adapter protein (ADAP) is a multifunctional scaffold that regulates T cell receptor-mediated activation of integrins via association with the SKAP55 adapter and the NF-κB pathway through interactions with both the CARMA1 adapter and serine/threonine kinase transforming growth factor β-activated kinase 1 (TAK1). ADAP-deficient T cells exhibit impaired proliferation following T cell receptor stimulation, but the contribution of these distinct functions of ADAP to this defect is not known. We demonstrate that loss of ADAP results in a G1-S transition block in cell cycle progression following T cell activation due to impaired accumulation of cyclin-dependent kinase 2 (Cdk2) and cyclin E. The CARMA1-binding site in ADAP is critical for mitogen-activated protein (MAP) kinase kinase 7 (MKK7) phosphorylation and recruitment to the protein kinase C θ (PKCθ) signalosome and subsequent c-Jun kinase (JNK)-mediated Cdk2 induction. Cyclin E expression following T cell receptor stimulation of ADAP-deficient T cells is transient and associated with enhanced cyclin E ubiquitination. Both the CARMA1- and TAK1-binding sites in ADAP are critical for restraining cyclin E ubiquitination and turnover independently of ADAP-dependent JNK activation. T cell receptor-mediated proliferation was most dramatically impaired by the loss of ADAP interactions with CARMA1 or TAK1 rather than SKAP55. Thus, ADAP coordinates distinct CARMA1-dependent control of key cell cycle proteins in T cells.
机译：粘附和脱粒促进衔接蛋白（ADAP）是一种多功能支架，通过与SKAP55衔接子和NF-κB途径的结合，通过与CARMA1衔接子和丝氨酸/苏氨酸激酶转化生长的相互作用来调节T细胞受体介导的整合素活化β因子活化激酶1（TAK1）。缺乏ADAP的T细胞在T细胞受体刺激后表现出增殖受损，但是ADAP的这些独特功能对该缺陷的贡献尚不清楚。我们证明，ADAP的丧失会导致T细胞活化后细胞周期进程中G 1 -S过渡阻滞，这归因于细胞周期蛋白依赖性激酶2（Cdk2）和细胞周期蛋白E的积累受损。 ADAP中的结合位点对于促分裂原激活蛋白（MAP）激酶激酶7（MKK7）磷酸化和募集到蛋白激酶Cθ（PKCθ）信号小体以及随后的c-Jun激酶（JNK）介导的Cdk2诱导至关重要。在T细胞受体刺激ADAP缺陷型T细胞后，细胞周期蛋白E的表达是短暂的，并与增强的细胞周期蛋白E泛素化有关。 ADAP中的CARMA1和TAK1结合位点对于独立于ADAP依赖的JNK激活来抑制细胞周期蛋白E泛素化和更新至关重要。 T细胞受体介导的增殖受到与CARMA1或TAK1而非SKAP55的ADAP相互作用丧失的最大影响。因此，ADAP协调不同的CARMA1依赖性控制T细胞中关键细胞周期蛋白。

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