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Biochim Biophys Acta Mol Cell Res. 2018 Jun;1865(6):920-931. doi: 10.1016/j.bbamcr.2018.03.013. Epub 2018 Apr 3.

Identification of a unique loss-of-function mutation in IGF1R and a crosstalk between IGF1R and Wnt/β-catenin signaling pathways.

Author information

1
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India.
2
School of Life Sciences, Central University of Himachal Pradesh, Kangra-176206, Himachal Pradesh, India.
3
Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh 226025, India.
4
Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, USA.
5
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India. Electronic address: jamal@iiim.res.in.

Abstract

IGF1R is a ubiquitous receptor tyrosine kinase that plays critical roles in cell proliferation, growth and survival. Clinical studies have demonstrated upregulation of IGF1R mediated signaling in a number of malignancies including colon, breast, and lung cancers. Overexpression of the IGF1R in these malignancies is associated with a poor prognosis and overall survival. IGF1R specific kinase inhibitors have failed in multiple clinical trials partly because of the complex nature of IGF1R signaling. Thus identifying new binding partners and allosteric sites on IGF1R are emerging areas of research. More recently, IGF1R has been shown to translocate into the nucleus and perform many functions. In this study, we generated a library of IGF1R deletion and point mutants to examine IGF1R subcellular localization and activation of downstream signaling pathways. We show that the nuclear localization of IGF1R is primarily defined by its cytoplasmic domain. We identified a cross-talk between IGF1R and Wnt/β-catenin signaling pathways and showed, for the first time, that IGF1R is associated with upregulation of TCF-mediated β-catenin transcriptional activity. Using loss-of-function mutants, deletion analysis and IGF1R specific inhibitor(s), we show that cytoplasmic and nuclear activities are two independent functions of IGF1R. Furthermore, we identified a unique loss-of-function mutation in IGF1R. This unique loss-of-function mutant retains only nuclear functions and sits in a pocket, outside ATP and substrate binding region, that is suited for designing allosteric inhibitors of IGF1R.

KEYWORDS:

IGF1R; PI3K/Akt; Receptor Tyrosine Kinases; Wnt/β-catenin signaling

PMID:
29621572
DOI:
10.1016/j.bbamcr.2018.03.013
[Indexed for MEDLINE]
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