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首页> 外文期刊>Current Biology: CB >Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component slimb
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Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component slimb

机译：果蝇刺猬信号转导因子Ci-155到阻遏物Ci-75的加工是通过直接结合SCF组分slimb介导的

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摘要

Signaling by extracellular Hedgehog (Hh) molecules is crucial for the correct allocation of cell fates and patterns of cell proliferation in humans and other organisms . Responses to Hh are universally mediated by regulating the activity and the proteolysis of the Gli family of transcriptional activators such that they induce target genes only in the presence of Hh . In the absence of Hh, the sole Drosophila Gli homolog, Cubitus interruptus (Ci), undergoes partial proteolysis to Ci-75, which represses key Hh target genes . This processing requires phosphorylation of full-length Ci (Ci-155) by protein kinase A (PKA), casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK3), as well as the activity of Slimb . Slimb is homologous to vertebrate beta-TRCP1, which binds as part of an SCF (Skp1/Cullin1/F-box) complex to a defined phosphopeptide motif to target proteins for ubiquitination and subsequent proteolysis . Here, we show that phosphorylation of Ci at the specific PKA, GSK-3, and CK1 sites required in vivo for partial proteolysis stimulates binding to Slimb in vitro. Furthermore, a consensus Slimb/beta-TRCP1 binding site from another protein can substitute for phosphorylated residues of Ci-155 to direct conversion to Ci-75 in vivo. From this, we conclude that Slimb binds directly to phosphorylated Ci-155 to initiate processing to Ci-75. We also explore the phosphorylated motifs in Ci that are recognized by Slimb and provide some evidence that silencing of Ci-155 by phosphorylation may involve more than binding to Slimb.
机译：细胞外刺猬（Hh）分子发出的信号对于正确分配人类和其他生物的细胞命运和细胞增殖模式至关重要。对Hh的反应普遍通过调节转录激活因子Gli家族的活性和蛋白水解来介导，这样它们仅在Hh存在时才诱导靶基因。在没有Hh的情况下，果蝇Gli的唯一同系物Cubitus interruptus（Ci）受到部分蛋白水解成Ci-75，从而抑制了关键的Hh靶基因。此过程需要蛋白激酶A（PKA），酪蛋白激酶1（CK1）和糖原合酶激酶3（GSK3）对全长Ci（Ci-155）进行磷酸化，以及Slimb的活性。 Slimb与脊椎动物β-TRCP1同源，后者作为SCF（Skp1 / Cullin1 / F-box）复合体的一部分与定义的磷酸肽基序结合，以靶向蛋白进行泛素化和随后的蛋白水解。在这里，我们显示在体内部分蛋白质水解所需的特定PKA，GSK-3和CK1位点上Ci的磷酸化刺激了Slimb在体外的结合。此外，来自另一种蛋白质的共有的Slimb / beta-TRCP1结合位点可以替代Ci-155的磷酸化残基，以在体内直接转化为Ci-75。据此，我们得出结论，Slimb直接与磷酸化的Ci-155结合以启动对Ci-75的加工。我们还探索了被Slimb识别的Ci中的磷酸化基序，并提供了一些证据表明通过磷酸化使Ci-155沉默可能不仅限于与Slimb结合。

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