Oncotarget

Research Papers:

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

Roberta Malaguarnera _, Maria Luisa Nicolosi, Antonella Sacco, Alaide Morcavallo, Veronica Vella, Concetta Voci, Michela Spatuzza, Shi-Qiong Xu, Renato V. Iozzo, Riccardo Vigneri, Andrea Morrione and Antonino Belfiore

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Oncotarget. 2015; 6:16084-16105. https://doi.org/10.18632/oncotarget.3177

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Abstract

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

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.


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