title: Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses.
abstract: The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression.Experiments in mouse fibroblasts co-transfected with the human IGF-IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired.These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR.
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Malaguarnera
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Nicolosi
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Alaide
authors.initials: A
authors.lastname: Morcavallo
authors.affiliation: Motor Sciences, School of Human and Social Sciences, Kore University of Enna, Enna, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Vella
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Voci
authors.affiliation: Institute of Neurological Sciences, National Research Council, Catania, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Spatuzza
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: Endocrinology, Department of Clinical and Sperimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vigneri
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
authors.affiliation: Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D000070819:Discoidin Domain Receptor 1; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000378:metabolism*
chemical_list: C000597236:IGF1R protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017451:Receptors, Somatomedin; D014443:Tyrosine; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1
keywords: DDR1; IGF-IR; breast cancer; insulin-like growth factor-I receptor
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