T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin
T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin
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DOI：
10.1073/pnas.0403382101
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发表时间：
2004-07-13
影响因子：
11.1
通讯作者：
Lodish, HF
中科院分区：
文献类型：
--
作者：
Hug, C;Wang, J;Lodish, HF
Acrp30/脂联素在肥胖和糖尿病个体的血清中减少，脂联素的遗传位点与代谢综合征有关。将重组脂联素给予饮食诱导的肥胖小鼠，可诱导体重减轻并改善胰岛素敏感性。在肌肉和肝脏中，脂联素刺激 AMP 激活的蛋白激酶活化和脂肪酸氧化。为了获得能够结合脂联素的表达克隆分子，我们将 C2C12 成肌细胞 cDNA 逆转录病毒表达文库转导到 Ba/F3 细胞中，并在与磁珠连接的重组脂联素上淘选感染的细胞。我们确定 T-钙粘蛋白是六聚体和高分子量脂联素的受体，但不是三聚体或球状脂联素的受体。只有真核表达的脂联素才能与 T-钙粘蛋白结合，这意味着脂联素的翻译后修饰对于结合至关重要。在免疫共沉淀研究中，缺乏形成六聚体和高分子量物质所需的保守 N 末端半胱氨酸残基的脂联素突变体不会结合 T-钙粘蛋白。尽管缺乏已知的细胞功能，T-钙粘蛋白在内皮细胞和平滑肌细胞中表达，并与脂联素相互作用。由于 T-钙粘蛋白是一种糖基磷脂酰肌醇锚定的细胞外蛋白，因此它可能充当尚未鉴定的信号受体的辅助受体，脂联素通过该信号受体传递代谢信号。
Acrp30/adiponectin is reduced in the serum of obese and diabetic individuals, and the genetic locus of adiponectin is linked to the metabolic syndrome. Recombinant adiponectin, administered to diet-induced obese mice, induced weight loss and improved insulin sensitivity. In muscle and liver, adiponectin stimulates AMP-activated protein kinase activation and fatty acid oxidation. To expression-clone molecules capable of binding adiponectin, we transduced a C2C12 myoblast cDNA retroviral expression library into Ba/F3 cells and panned infected cells on recombinant adiponectin linked to magnetic beads. We identified T-cadherin as a receptor for the hexameric and high-molecular-weight species of adiponectin but not for the trimeric or globular species. Only eukaryotically expressed adiponectin bound to T-cadherin, implying that posttranslational modifications of adiponectin are critical for binding. An adiponectin mutant lacking a conserved N-terminal cysteine residue required for formation of hexamer and high-molecular-weight species did not bind T-cadherin in coimmunoprecipitation studies. Although lacking known cellular functions, T-cadherin is expressed in endothelial and smooth muscle cells, where it is positioned to interact with adiponectin. Because T-cadherin is a glycosylphosphatidylinositol-anchored extracellular protein, it may act as a coreceptor for an as-yet-unidentified signaling receptor through which adiponectin transmits metabolic signals.