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

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.

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

“…Here, we showed that DB treatment not only suppressed colon tumorigenesis, but also CSC phenotypes. DB-medicated CSC-inhibitory effects were associated with the decreased expression of the IGF downstream oncogenic marker, mTOR/STAT3, as well as the stemness marker, β-catenin, both of which have been reported to contribute to treatment failure and the recurrence of colon cancer [ 23 , 34 , 35 ].…”

Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy

“…In addition, IGF-IR interacts with T cell factor (TCF) and promotes the expression of β-catenin/TCF targets including cyclin D1 and axin 2 [87]. Of note, the kinase activity of IGF-IR is not required for its nuclear translocation and activation of transcription [88]. Nevertheless, the nuclear IGF-IR still acts as a kinase to phosphorylate its nuclear partners.…”

miRNA‑29a inhibits colon cancer growth by regulation of the PTEN/Akt/GSK3β and Wnt/β‑catenin signaling pathways

“…GSK3β is the major regulatory enzyme of numerous intracellular signal transduction pathways (14). Regulating GSK3β activity is able to affect the growth and apoptosis of different tumor types, including colon, lung and breast cancer (15); however, experiments on the effect of regulating GSK3β activity on tumor cell proliferation have led to contrasting results (12)(13)(14)(15).…”

“…The Wnt/β-catenin signaling pathway is associated with tumor development (15). In breast, liver, stomach, thyroid, lung and prostate cancer, as well as melanoma and other malignant tumor types, the abnormal activation of the Wnt/β-catenin signaling pathway and the downregulation of expression or the inactivation of the pathway inhibitory proteins, such as Dickkopf Wnt signaling pathway inhibitor 1 (DKKI) or Wnt inhibitory factor 1 (WIF), have been determined (15,16).…”

“…In breast, liver, stomach, thyroid, lung and prostate cancer, as well as melanoma and other malignant tumor types, the abnormal activation of the Wnt/β-catenin signaling pathway and the downregulation of expression or the inactivation of the pathway inhibitory proteins, such as Dickkopf Wnt signaling pathway inhibitor 1 (DKKI) or Wnt inhibitory factor 1 (WIF), have been determined (15,16). The abnormal activation of the pathway is an early event in colorectal cancer, and also indicates its importance in development.…”