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双泛素途径对Hh/Gli信号的调控

Regulation of Hh/Gli signaling by dual ubiquitin pathways.

作者信息

Jiang Jin

机构信息

Center for Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 75390, USA.

出版信息

Cell Cycle. 2006 Nov 1;5(21):2457-63. doi: 10.4161/cc.5.21.3406. Epub 2006 Sep 14.

Abstract

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 SCF(Slimb/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.

摘要

刺猬信号通路(Hh)在动物发育过程中调控细胞生长和模式形成。该通路的几个组成部分出现功能异常,包括关键转录效应因子Ci/Gli蛋白,会导致多种人类疾病,包括几种恶性肿瘤。Ci/Gli的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作用。在没有Hh的情况下,Ci/Gli会被蛋白水解加工成截短形式,作为Hh通路的转录抑制因子发挥作用。Ci的加工由一种SCF(Ski1/Cul1/F-box蛋白)泛素连接酶介导,其中F-box蛋白Slimb/β-TRCP将Ci与泛素连接酶相连。最近在果蝇和哺乳动物培养细胞中的研究表明,PKA、GSK3和CKI对Ci/Gli的顺序磷酸化产生了多个对接位点,可招募SCF(Slimb/β-TRCP),进而促进Ci/Gli的泛素化,随后经蛋白酶体介导进行加工。最近,已鉴定出一种由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,它通过降解全长Ci在负反馈回路中发挥作用,以微调Hh信号反应。在Hh信号协调细胞增殖和分化的眼成虫盘中,HIB在分化细胞中高度表达,以防止异常的Hh信号活性并确保正常的眼睛发育。HIB及其在脊椎动物中的同源物在组织和发育阶段的特异性表达,可能为确保Hh信号在时空控制上的精确性提供一种保守机制。

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