Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses
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Roberta Malaguarnera1,*, Maria Luisa Nicolosi1,*, Antonella Sacco1, Alaide Morcavallo1, Veronica Vella2, Concetta Voci1, Michela Spatuzza3, Shi-Qiong Xu4, Renato V. Iozzo5, Riccardo Vigneri6, Andrea Morrione4, Antonino Belfiore1
1Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
2Motor Sciences, School of Human and Social Sciences, Kore University of Enna, Enna, Italy
3Institute of Neurological Sciences, National Research Council, Catania, Italy
4Department of Urology and Biology of Prostate Cancer Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
5Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
6Endocrinology, Department of Clinical and Sperimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
*These authors have contributed equally to this work
Antonino Belfiore, e-mail: firstname.lastname@example.org
Andrea Morrione, e-mail: email@example.com
Keywords: IGF-IR, insulin-like growth factor-I receptor, DDR1, breast cancer
Received: September 01, 2014 Accepted: January 25, 2015 Published: March 28, 2015
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.
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