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.