STAM and hrs down-regulate ciliary TRP receptors
STAM and hrs down-regulate ciliary TRP receptors
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DOI：
10.1091/mbc.e07-03-0239
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发表时间：
2007-09-01
影响因子：
3.3
通讯作者：
Barr, Maureen M.
中科院分区：
文献类型：
--
作者：
Hu, Jinghua;Wittekind, Samuel G.;Barr, Maureen M.
纤毛具有膜受体、通道和信号传导成分，其定位和功能必须受到严格控制。在哺乳动物肾上皮的初级纤毛和秀丽隐杆线虫神经元的感觉纤毛中，多囊蛋白-1 (PC1) 和瞬时受体多囊蛋白-2 通道（TRPP2 或 PC2）一起作为机械感觉受体通道复合物发挥作用。尽管多囊蛋白在感觉转导中很重要，但调节多囊蛋白活性和定位或一般睫状膜受体的机制仍然知之甚少。我们证明信号转导接头分子 STAM-1A 与线虫 LOV-1 (PC1) 相互作用，并且 STAM 与早期内体上肝细胞生长因子调节的酪氨酸激酶底物 (Hrs) 一起发挥作用，指导 LOV-1-PKD-2 复合物进行溶酶体降解。在 stam-1 突变体中，LOV-1 和 PKD-2 都不适当地积聚在纤毛基部。相反，STAM 或 Hrs 的过度表达会促进 PKD-2 从纤毛中去除，最终导致感觉行为缺陷。这些数据表明，STAM-Hrs 复合物可下调酵母和哺乳动物细胞表面的配体激活生长因子受体，还调节纤毛 PC1 受体-TRPP2 复合物的定位和信号传导。
Cilia are endowed with membrane receptors, channels, and signaling components whose localization and function must be tightly controlled. In primary cilia of mammalian kidney epithelia and sensory cilia of Caenorhabditis elegans neurons, polycystin-1 (PC1) and transient receptor polycystin-2 channel (TRPP2 or PC2), function together as a mechanosensory receptor-channel complex. Despite the importance of the polycystins in sensory transduction, the mechanisms that regulate polycystin activity and localization, or ciliary membrane receptors in general, remain poorly understood. We demonstrate that signal transduction adaptor molecule STAM-1A interacts with C. elegans LOV-1 (PC1), and that STAM functions with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) on early endosomes to direct the LOV-1-PKD-2 complex for lysosomal degradation. In a stam-1 mutant, both LOV-1 and PKD-2 improperly accumulate at the ciliary base. Conversely, overexpression of STAM or Hrs promotes the removal of PKD-2 from cilia, culminating in sensory behavioral defects. These data reveal that the STAM-Hrs complex, which down-regulates ligand-activated growth factor receptors from the cell surface of yeast and mammalian cells, also regulates the localization and signaling of a ciliary PC1 receptor-TRPP2 complex.