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

Authors

Roberta Malaguarnera, Department of Health Sciences, University Magna Graecia of Catanzaro
Maria Luisa Nicolosi, Department of Health Sciences, University Magna Graecia of Catanzaro
Antonella Sacco, Department of Health Sciences, University Magna Graecia of Catanzaro
Alaide Morcavallo, Department of Health Sciences, University Magna Graecia of Catanzaro
Veronica Vella, Motor Sciences, School of Human and Social Sciences, Kore University of Enna
Concetta Voci, Department of Health Sciences, University Magna Graecia of Catanzaro
Michela Spatuzza, Institute of Neurological Sciences, National Research Council, Catania, Italy
Shi-Qiong Xu, Endocrine Mechanisms and Hormone Action Program, Department of Urology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Renato V Iozzo, Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Riccardo Vigneri, Department of Clinical and Sperimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
Andrea Morrione, Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Antonino Belfiore, Department of Health Sciences, University Magna Graecia of Catanzaro

Document Type

Article

Publication Date

6-30-2015

Comments

This article has been peer reviewed. It was published in: Oncotarget.

Volume 6, Issue 18, 2015, Pages 16084-16105.

The published version is available at http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=3177&pubmed-linkout=1

Copyright © 2015 the authors

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.

Recommended Citation

Malaguarnera, Roberta; Nicolosi, Maria Luisa; Sacco, Antonella; Morcavallo, Alaide; Vella, Veronica; Voci, Concetta; Spatuzza, Michela; Xu, Shi-Qiong; Iozzo, Renato V; Vigneri, Riccardo; Morrione, Andrea; and Belfiore, Antonino, "Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses." (2015). Kimmel Cancer Center Faculty Papers. Paper 77.
https://jdc.jefferson.edu/kimmelccfp/77

PubMed ID

25840417