Type II transforming growth factor-beta receptor recycling is dependent upon the clathrin adaptor protein Dab2.
Type II transforming growth factor-beta receptor recycling is dependent upon the clathrin adaptor protein Dab2.
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DOI：
10.1091/mbc.e09-12-1019
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发表时间：
2010-11-15
影响因子：
3.3
通讯作者：
Leof EB
中科院分区：
文献类型：
--
作者：
Penheiter SG;Singh RD;Repellin CE;Wilkes MC;Edens M;Howe PH;Pagano RE;Leof EB
转化生长因子-β受体的循环是由网格蛋白接头Dab2蛋白调控的。在缺乏Dab2的情况下，受体定位于核周区域，因为它们无法从早期内体抗原1阳性的早期内体转移到rab11阳性的内体循环室。转化生长因子(TGF)-β家族蛋白与被称为I型和II型受体的跨膜丝氨酸/苏氨酸激酶形成异质复合物。配体结合启动信号级联，产生各种细胞类型特异性表型。尽管已有大量研究调查了TGF-β信号传导的调控活性，但关于TGF-β受体亚基的内吞和转运过程的研究相对较少。在目前的研究中，我们研究了网格蛋白相关分选蛋白Disabled-2 （Dab2）在TGF-β受体内吞作用中的作用。虽然小干扰rna介导的Dab2敲低对各种网格蛋白依赖性（即TGF-β、低密度脂蛋白或转铁蛋白）或非依赖性（即LacCer）货物的内化没有影响，但TGF-β受体的再循环被取消。Dab2的缺失导致早期内体抗原1阳性内体增大，反映了货物无法从早期内体运输到内体再循环室，并且如先前所述，Smad2磷酸化减少。这些结果支持了一种模型，即Dab2在间质细胞中作为TGF-β受体循环和Smad2磷酸化所需的多功能适配器。
Transforming growth factor-β receptor recycling is regulated by the clathrin adaptor Dab2 protein. In the absence of Dab2, receptors localize in a perinuclear locale because they are unable to transit from the early endosomal antigen 1-positive early endosome to the Rab11-positive endosomal recycling compartment. Transforming growth factor (TGF)-β family proteins form heteromeric complexes with transmembrane serine/threonine kinases referred to as type I and type II receptors. Ligand binding initiates a signaling cascade that generates a variety of cell type-specific phenotypes. Whereas numerous studies have investigated the regulatory activities controlling TGF-β signaling, there is relatively little information addressing the endocytic and trafficking itinerary of TGF-β receptor subunits. In the current study we have investigated the role of the clathrin-associated sorting protein Disabled-2 (Dab2) in TGF-β receptor endocytosis. Although small interfering RNA-mediated Dab2 knockdown had no affect on the internalization of various clathrin-dependent (i.e., TGF-β, low-density lipoprotein, or transferrin) or -independent (i.e., LacCer) cargo, TGF-β receptor recycling was abrogated. Loss of Dab2 resulted in enlarged early endosomal antigen 1-positive endosomes, reflecting the inability of cargo to traffic from the early endosome to the endosomal recycling compartment and, as documented previously, diminished Smad2 phosphorylation. The results support a model whereby Dab2 acts as a multifunctional adaptor in mesenchymal cells required for TGF-β receptor recycling as well as Smad2 phosphorylation.