Abstract
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.
Highlights
The spatial and temporal distribution of the components of different signaling pathways is exquisitely controlled
We show that the impairment of internalization augments the levels of cell surface pro-TGF-␣ and, the activation of the epidermal growth factor receptor (EGFR), showing that the dynamics of the growth factor at the cell surface have a direct impact on its activity
The results presented here illustrate the tight links between intracellular traffic and signal transduction
Summary
The spatial and temporal distribution (i.e. the trafficking) of the components of different signaling pathways is exquisitely controlled. Cells were incubated for 1 h at 37 °C in DMEM-Hepes with EGF (100 ng/ml) and the ectodomain shedding inhibitor BB-94 (25 M), allowing recycling of the internalized pro-TGF-␣-anti-HA complexes to the cell surface.
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