Martínez-Arca Sonia, Bech-Serra Joan Josep, Hurtado-Küttner Miguel, Borroto Aldo, Arribas Joaquín
Medical Oncology Research Program, Vall d'Hebron Research Institute University Hospital, 119-129 Psg. Vall d'Hebron, Barcelona 08035, Spain.
J Biol Chem. 2005 Nov 4;280(44):36970-7. doi: 10.1074/jbc.M504425200. Epub 2005 Aug 29.
Impairments in signal transduction, leading to the regulation of cell proliferation, differentiation, or migration are frequently the cause of cancer. Since the accurate spatial and temporal location of their components is crucial to ensure the correct regulation of these signaling pathways, it could be anticipated that defects in intracellular trafficking are at the base of certain neoplasias. However, the trafficking of many components of pathways frequently up-regulated in cancers, such as the epidermal growth factor receptor (EGFR) pathway, are largely unknown. Here, we show that the pro-transforming growth factor-alpha (pro-TGF-alpha), a prototypical EGFR ligand, is endocytosed from the cell surface via a clathrin-dependent pathway. Internalized pro-TGF-alpha does not progress to the lysosome; instead, it is delivered to the cell surface via recycling endosomes. To analyze the functional meaning of the internalization of pro-TGF-alpha, we used a deletion construct that is normally transported to the cell surface but is deficiently endocytosed. Due to this impairment, the levels of this construct at the cell surface are dramatically augmented. Consequently, the deletion construct displays a higher EGFR-activating ability, revealing a link between the trafficking of pro-TGF-alpha and the signaling by the EGFR and opening the possibility that defects in the trafficking of the growth factor may contribute to the development of tumors.
信号转导受损会导致细胞增殖、分化或迁移的调控异常，这常常是癌症的起因。由于信号转导通路各组分精确的时空定位对于确保这些信号通路的正确调控至关重要，可以推测细胞内运输缺陷是某些肿瘤形成的基础。然而，癌症中经常上调的许多信号通路组分的运输，如表皮生长因子受体（EGFR）通路，在很大程度上尚不清楚。在此，我们表明前转化生长因子-α（pro-TGF-α），一种典型的EGFR配体，通过网格蛋白依赖途径从细胞表面内吞。内化的pro-TGF-α不会进入溶酶体；相反，它通过回收内体被递送至细胞表面。为了分析pro-TGF-α内化的功能意义，我们使用了一种缺失构建体，该构建体通常被运输到细胞表面，但内吞缺陷。由于这种缺陷，该构建体在细胞表面的水平显著增加。因此，缺失构建体显示出更高的EGFR激活能力，揭示了pro-TGF-α运输与EGFR信号传导之间的联系，并开启了生长因子运输缺陷可能导致肿瘤发生的可能性。
