Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases.
Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases.
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DOI：
10.1016/j.bbamcr.2012.10.010
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发表时间：
2013-01
影响因子：
5.1
通讯作者：
Band, Hamid
中科院分区：
文献类型：
--
作者：
Mohapatra, Bhopal;Ahmad, Gulzar;Nadeau, Scott;Zutshi, Neha;An, Wei;Scheffe, Sarah;Dong, Lin;Feng, Dan;Goetz, Benjamin;Arya, Priyanka;Bailey, Tameka A.;Palermo, Nicholas;Borgstahl, Gloria E. O.;Natarajan, Amarnath;Raja, Srikumar M.;Naramura, Mayumi;Band, Vimla;Band, Hamid
关键词：
蛋白酪氨酸激酶（PTK）在发育、组织稳态和对环境挑战的反应期间协调对细胞外刺激和细胞-细胞相互作用的广谱细胞反应。因此，在生物学和医学中，对确保生理PTK功能的调节机制和在疾病（例如癌症）期间这些调节过程的潜在畸变的理解具有广泛的兴趣。除了磷酸酪氨酸磷酸酶的预期作用之外，最近的研究已经揭示了用泛素共价修饰活化的PTK作为其负调节的关键机制的关键作用。Cbl蛋白家族的成员（哺乳动物中的Cbl、Cbl-b和Cbl-c）已成为占主导地位的“活化的PTK选择性”泛素连接酶。结构、生物化学和细胞生物学研究已经确定，Cbl蛋白依赖性泛素化靶向活化的PTK，通过促进其内吞分选进入溶酶体或通过促进其蛋白酶体降解来降解。该机制还靶向以PTK活化依赖性方式与Cbl蛋白相关的PTK信号传导中间体。细胞和动物研究已经确定，相对广泛表达的哺乳动物Cbl家族成员Cbl和Cbl-b发挥关键的生理作用，包括其防止正常免疫应答转变为自身免疫性疾病和作为肿瘤抑制剂的关键功能;后一种功能已经从将Cbl中的突变与人类白血病联系起来的人类研究中得到验证。这些较新的见解与胚胎致死率在小鼠与联合删除的Cbl和Cbl-b基因表明一个未被重视的作用的Cbl家族蛋白，并通过暗示的泛素依赖性控制激活的PTKs，在干细胞/祖细胞的维护。未来对现有和新兴动物模型及其各种细胞谱系的研究应有助于测试进化上保守的Cbl家族蛋白介导的、泛素依赖的、激活的PTKs在生理学和疾病中的负调控的更广泛意义。
Protein tyrosine kinases (PTKs) coordinate a broad spectrum of cellular responses to extracellular stimuli and cell–cell interactions during development, tissue homeostasis, and responses to environmental challenges. Thus, an understanding of the regulatory mechanisms that ensure physiological PTK function and potential aberrations of these regulatory processes during diseases such as cancer are of broad interest in biology and medicine. Aside from the expected role of phospho-tyrosine phosphatases, recent studies have revealed a critical role of covalent modification of activated PTKs with ubiquitin as a critical mechanism of their negative regulation. Members of the Cbl protein family (Cbl, Cbl-b and Cbl-c in mammals) have emerged as dominant “activated PTK-selective” ubiquitin ligases. Structural, biochemical and cell biological studies have established that Cbl protein-dependent ubiquitination targets activated PTKs for degradation either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation. This mechanism also targets PTK signaling intermediates that become associated with Cbl proteins in a PTK activation-dependent manner. Cellular and animal studies have established that the relatively broadly expressed mammalian Cbl family members Cbl and Cbl-b play key physiological roles, including their critical functions to prevent the transition of normal immune responses into autoimmune disease and as tumor suppressors; the latter function has received validation from human studies linking mutations in Cbl to human leukemia. These newer insights together with embryonic lethality seen in mice with a combined deletion of Cbl and Cbl-b genes suggest an unappreciated role of the Cbl family proteins, and by implication the ubiquitin-dependent control of activated PTKs, in stem/progenitor cell maintenance. Future studies of existing and emerging animal models and their various cell lineages should help test the broader implications of the evolutionarily-conserved Cbl family protein-mediated, ubiquitin-dependent, negative regulation of activated PTKs in physiology and disease.
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影响因子：
5.3
作者：
Bonita, DP;Miyake, S;Band, H
通讯作者：
Band, H
影响因子：
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作者：
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