Regulation of Hh/Gli signaling by dual ubiquitin pathways
Regulation of Hh/Gli signaling by dual ubiquitin pathways
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DOI：
10.4161/cc.5.21.3406
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发表时间：
2006-11-01
期刊：
影响因子：
4.3
通讯作者：
Jiang, Jin
中科院分区：
文献类型：
--
作者：
Jiang, Jin
Hedgehog （Hh）信号通路控制着动物发育过程中的细胞生长和模式。包括关键转录效应因子Ci/Gli蛋白在内的几种途径组分的功能障碍导致多种人类疾病，包括几种恶性肿瘤。Ci/Gli活性受多层调控机制控制，其中最突出的是泛素介导的蛋白水解。在Hh缺失的情况下，Ci/Gli被蛋白水解加工成截断的形式，作为Hh通路的转录抑制因子。Ci加工由SCF （Skip1/Cul1/F-box蛋白）泛素连接酶介导，其中F-box蛋白slim / β - trcp将Ci连接到泛素连接酶。最近对果蝇和哺乳动物培养细胞的研究表明，PKA、GSK3和CKI对Ci/Gli的顺序磷酸化产生了多个对接位点，这些对接位点可以招募scfsllimb / β - trcp，然后促进Ci/Gli泛素化，随后是蛋白酶体介导的加工。最近，一种由BTB （Broad Complex， Tramtrack和Bric a Brac）蛋白HIB （Hh诱导的MATH和BTB蛋白）和Cullin 3 （Cul3）组成的E3泛素连接酶被发现在一个负反馈回路中通过降解全长Ci来调节Hh信号反应。在Hh信号协调细胞增殖和分化的眼影像盘中，HIB在分化细胞中高表达，以防止Hh信号活动异常，确保眼睛正常发育。HIB及其同源物在脊椎动物中的组织和发育阶段特异性表达可能为Hh信号的时空精确控制提供了一种保守的机制。
The Hedgehog (Hh) signaling pathway governs cell growth and patterning in animal development. Malfunction of several pathway components, including the key transcriptional effector Ci/Gli proteins, leads to a variety of human disorders including several malignancies. Ci/Gli activity is controlled by multi-layered regulatory mechanisms, the most prominent of which is the ubiquitin - mediated proteolysis. In the absence of Hh, Ci/Gli is proteolytically processed into a truncated form that functions as a transcriptional repressor of the Hh pathway. Ci processing is mediated by an SCF (Skip1/Cul1/F-box protein) ubiquitin ligase in which the F - box protein Slimb/beta-TRCP bridges Ci to the ubiquitin ligase. Recent studies in Drosophila and mammalian cultured cells have demonstrated that sequential phosphorylation of Ci/Gli by PKA, GSK3, and CKI creates multiple docking sites that can recruit SCFSlimb/beta-TRCP, which then promotes Ci/Gli ubiquitination followed by proteasome - mediated processing. Recently, an E3 ubiquitin ligase consisting of the BTB (Broad Complex, Tramtrack, and Bric a Brac) protein HIB (Hh induced MATH and BTB protein) and Cullin 3 (Cul3) has been identified that acts in a negative feedback loop to fine - tune Hh signaling responses by degrading full length Ci. In eye imaginal discs where Hh signals coordinate cell proliferation and differentiation, HIB is highly expressed in the differentiating cells to prevent aberrant Hh signaling activity and ensure normal eye development. Tissue - and developmental stage - specific expression of HIB and its homologs in vertebrates may provide a conserved mechanism for ensuring precision in spatial and temporal control of Hh signaling.