title: Recycling of cell surface pro-transforming growth factor-{alpha} regulates epidermal growth factor receptor activation.
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.
authors.affiliation: Medical Oncology Research Program, Vall d'Hebron Research Institute University Hospital, 119-129 Psg. Vall d'Hebron, Barcelona 08035, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez-Arca
authors.forename: Joan Josep
authors.initials: JJ
authors.lastname: Bech-Serra
authors.forename: Miguel
authors.initials: M
authors.lastname: Hurtado-Küttner
authors.forename: Aldo
authors.initials: A
authors.lastname: Borroto
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002966:Clathrin / Q000378:metabolism; D006224:Cricetinae; D004285:Dogs; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D017384:Sequence Deletion; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
chemical_list: D002966:Clathrin; D011498:Protein Precursors; D016211:Transforming Growth Factor alpha; C052268:protransforming growth factor alpha; D066246:ErbB Receptors