Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses

// Roberta Malaguarnera 1, * , Maria Luisa Nicolosi 1, * , Antonella Sacco 1 , Alaide Morcavallo 1 , Veronica Vella 2 , Concetta Voci 1 , Michela Spatuzza 3 , Shi-Qiong Xu 4 , Renato V. Iozzo 5 , Riccardo Vigneri 6 , Andrea Morrione 4 , Antonino Belfiore 1 1 Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy 2 Motor Sciences, School of Human and Social Sciences, Kore University of Enna, Enna, Italy 3 Institute of Neurological Sciences, National Research Council, Catania, Italy 4 Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 5 Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 6 Endocrinology, Department of Clinical and Sperimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy * These authors have contributed equally to this work Correspondence to: Antonino Belfiore, e-mail: belfiore@unicz.it Andrea Morrione, e-mail: andrea.morrione@jefferson.edu Keywords: IGF-IR, insulin-like growth factor-I receptor, DDR1, breast cancer Received: September 01, 2014      Accepted: January 25, 2015      Published: March 28, 2015 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.