Lipid modifications of Sonic hedgehog ligand dictate cellular reception and signal response.
Lipid modifications of Sonic hedgehog ligand dictate cellular reception and signal response.
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DOI：
10.1371/journal.pone.0021353
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Cooper MK
中科院分区：
文献类型：
--
作者：
Grover VK;Valadez JG;Bowman AB;Cooper MK
Sonic hedgehog（Shh）信号传导在胚胎发育、组织稳态和肿瘤发生期间调节细胞生长。分泌的Shh蛋白的浓度依赖性细胞反应对于组织图案化是必不可少的。Shh配体被两个脂质部分（胆固醇和棕榈酸酯）共价修饰，并且已知它们的疏水性质支配可溶性多聚体Shh复合物的细胞释放和形成。然而，脂质部分对细胞接收和信号响应的影响还没有得到很好的理解。我们分析了完全脂化的Shh和突变形式，以消除NIH3T3小鼠胚胎成纤维细胞中的一种或两种加合物。整合重组Shh蛋白浓度、细胞定位和信号传导效力的定量测量以确定每种脂质加合物对配体细胞定位和信号传导效力的贡献。我们表明，脂质修饰是需要细胞接收，这两种加合物是足以赋予细胞协会，胆固醇加合物锚定配体的质膜和棕榈酸酯加合物增强配体内化。我们进一步表明，信号传导效力直接与细胞浓度的Shh配体。这项研究的结果表明，脂质修饰的Shh决定细胞的浓度和效力，揭示了互补功能的疏水修饰的形态发生信号通过衰减细胞释放和增强接收的Shh蛋白在靶组织。
Sonic hedgehog (Shh) signaling regulates cell growth during embryonic development, tissue homeostasis and tumorigenesis. Concentration-dependent cellular responses to secreted Shh protein are essential for tissue patterning. Shh ligand is covalently modified by two lipid moieties, cholesterol and palmitate, and their hydrophobic properties are known to govern the cellular release and formation of soluble multimeric Shh complexes. However, the influences of the lipid moieties on cellular reception and signal response are not well understood. We analyzed fully lipidated Shh and mutant forms to eliminate one or both adducts in NIH3T3 mouse embryonic fibroblasts. Quantitative measurements of recombinant Shh protein concentration, cellular localization, and signaling potency were integrated to determine the contributions of each lipid adduct on ligand cellular localization and signaling potency. We demonstrate that lipid modification is required for cell reception, that either adduct is sufficient to confer cellular association, that the cholesterol adduct anchors ligand to the plasma membrane and that the palmitate adduct augments ligand internalization. We further show that signaling potency correlates directly with cellular concentration of Shh ligand. The findings of this study demonstrate that lipid modification of Shh determines cell concentration and potency, revealing complementary functions of hydrophobic modification in morphogen signaling by attenuating cellular release and augmenting reception of Shh protein in target tissues.
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