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Smoothened (SMO) regulates insulin-like growth factor 1 receptor (IGF1R) levels and protein kinase B (AKT) localization and signaling

Abstract

The oncoprotein Smoothened (SMO), a Frizzled-class-G-protein-coupled receptor, is the central transducer of hedgehog (Hh) signaling. While canonical SMO signaling is best understood in the context of cilia, evidence suggests that SMO has other functions in cancer biology that are unrelated to canonical Hh signaling. Herein, we provided evidence that elevated levels of human SMO show a strong correlation with elevated levels of insulin-like growth factor 1 receptor (IGF1R) and reduced survival in diffuse large B-cell lymphoma (DLBCL). As an integral component of raft microdomains, SMO plays a fundamental role in maintaining the levels of IGF1R in lymphoma and breast cancer cells as well IGF1R-associated activation of protein kinase B (AKT). Silencing of SMO increases lysosomal degradation and favors a localization of IGF1R to late endosomal compartments instead of early endosomal compartments from which much of the receptor would normally recycle. In addition, loss of SMO interferes with the lipid raft localization and retention of the remaining IGF1R and AKT, thereby disrupting the primary signaling context for IGF1R/AKT. This activity of SMO is independent of its canonical signaling and represents a novel and clinically relevant contribution to signaling by the highly oncogenic IGF1R/AKT signaling axis.

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Fig. 1: Elevated protein levels of SMO correlate with high IGF1R and poor survival in DLBCL.
Fig. 2: SMO enhances IGF1R-mediated activation of AKT.
Fig. 3: SMO stabilizes IGF1R protein levels independent of canonical signaling.
Fig. 4: Loss of SMO redirects IGF1R to late endosomes and lysosomal degradation.
Fig. 5: SMO localizes to raft microdomains and stabilizes IGF1R and pAKT levels in this compartment.

Data availability

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. James K. Chen (Department of Chemical and Systems Biology, Stanford University School of Medicine) for providing the SMO−/− (MEF) cells. We also thank Dr. Amit Deepak Amin for helpful comments for the manuscript. We acknowledge the University of Miami/Sylvester Comprehensive Cancer Center Histology Core and the Biorepository and Tissue Procurement Facility. This work has been supported by research funds from National Cancer Institute, National Institute of Health (grant R01CA222918) (to R.L. and F.V.), Sylvester Comprehensive Cancer Center/University of Miami (to R.L. and F.V.), the American Society of Hematology (ASH) bridge award (to F.V.) and Woman Cancer Association of Florida (to R.L.).

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Contributions

Conception and design: N.K.A., R.L. and F.V. Development of methodology: N.K.A., R.L. and F.V. Acquisition of the data: N.K.A., C.H.K., K.K., A.V., S.S., S.M., R.L. and F.V. Analysis and interpretation of the data (e.g., statistical analysis, biostatistics, computational analysis): N.K.A., R.L. and F.V. Writing, review, and/or revision of the manuscript: N.K.A., D.B., F.V. and R.L. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): N.K.A., R.L. and F.V. Study supervision: R.L. and F.V.

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Correspondence to Francisco Vega or Ralf Landgraf.

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Tissue specimens were collected from Sylvester Comprehensive Cancer Center, University of Miami under the approved institutional review board committee. The study was conducted in accordance with the declaration of Helsinki.

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Agarwal, N.K., Kim, CH., Kunkalla, K. et al. Smoothened (SMO) regulates insulin-like growth factor 1 receptor (IGF1R) levels and protein kinase B (AKT) localization and signaling. Lab Invest 102, 401–410 (2022). https://doi.org/10.1038/s41374-021-00702-6

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