Molecular pathways: cbl proteins in tumorigenesis and antitumor immunity-opportunities for cancer treatment.
Molecular pathways: cbl proteins in tumorigenesis and antitumor immunity-opportunities for cancer treatment.
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DOI：
10.1158/1078-0432.ccr-13-2490
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发表时间：
2015-04-15
期刊：
影响因子：
--
通讯作者：
Lipkowitz S
中科院分区：
文献类型：
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作者：
Liyasova MS;Ma K;Lipkowitz S
Cbl蛋白是通过许多酪氨酸激酶依赖性途径调节信号传导的泛素连接酶（E3）家族。一个主要功能是通过活性受体酪氨酸激酶（RTK）的遍在化来负调节受体酪氨酸激酶（RTK）信号传导，靶向它们运输到溶酶体进行降解。此外，Cbl介导的泛素化可以通过改变蛋白质的细胞定位而不降解来调节信号蛋白的功能。除了它们作为E3的作用之外，Cbl蛋白通过充当衔接蛋白在信号传导中发挥积极作用，衔接蛋白可以将信号传导分子募集到活性RTK。Cbl-b是第二个家族成员，负调节CD 8 T细胞的共刺激途径，也负调节自然杀伤（NK）细胞功能。Cbl蛋白的不同功能及其在癌症发展和免疫应答调节中的作用提供了多种治疗机会。在大约5%的骨髓肿瘤中描述了Ebl突变，该突变使阴性E3功能失活，同时维持阳性衔接子功能。理解信号通路（例如，Fms样酪氨酸激酶3（Flt 3）、PI-3激酶和信号转导子和转录激活子（Stat））如何被Cbl中的这些突变失调已经确定了用于骨髓肿瘤治疗的潜在靶点。相反，Cbl-b的丧失导致增加的适应性和先天性抗肿瘤免疫，这表明抑制Cbl-b可能是在多种肿瘤中增加抗肿瘤免疫的手段。因此，靶向由Cbl蛋白调节的途径可能为治疗癌症提供有吸引力的机会。
The Cbl proteins are a family of ubiquitin ligases (E3s) that regulate signaling through many tyrosine kinase dependent pathways. A predominant function is to negatively regulate receptor tyrosine kinase (RTK) signaling by ubiquitination of active RTKs, targeting them for trafficking to the lysosome for degradation. Also, Cbl-mediated ubiquitination can regulate signaling protein function by altered cellular localization of proteins without degradation. In addition to their role as E3s, Cbl proteins play a positive role in signaling by acting as adaptor proteins which can recruit signaling molecules to the active RTKs. Cbl-b, a second family member, negatively regulates the costimulatory pathway of CD8 T-cells and also negatively regulates Natural Killer (NK) cell function. The different functions of Cbl proteins, and their roles both in the development of cancer and the regulation of immune responses provide multiple therapeutic opportunities. Mutations in Cbl which inactivate the negative E3 function while maintaining the positive adaptor function have been described in approximately 5% of myeloid neoplasms. Understanding how the signaling pathways (e.g. Fms-like tyrosine kinase 3 (Flt3), PI-3 kinase, and signal transducer and activator of transcription (Stat)) are dysregulated by these mutations in Cbl has identified potential targets for therapy of myeloid neoplasms. Conversely, the loss of Cbl-b leads to increased adaptive and innate antitumor immunity suggesting that inhibiting Cbl-b may be a means to increase antitumor immunity across a wide variety of tumors. Thus, targeting the pathways regulated by Cbl proteins may provide attractive opportunities for treating cancer.