Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses
Nicolosi, Maria Luisa
Iozzo, Renato V.
Permanent link to this recordhttp://hdl.handle.net/20.500.12613/7089
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AbstractThe 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.
CitationMalaguarnera R., Nicolosi M. Luisa, Sacco A., Morcavallo A., Vella V., Voci C., Spatuzza M., Xu S., Iozzo R. V., Vigneri R., Morrione A., Belfiore A. Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses. Oncotarget. 2015; 6: 16084-16105. Retrieved from https://www.oncotarget.com/article/3177/text/
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Has partOncotarget, Vol. 6, No. 18
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