Novel Regulation of IGF1R by Ubiquilin1

Background Insulin‐like Growth Factor‐1 Receptor (IGF1R) is a receptor tyrosine kinase ubiquitously expressed on cell surfaces of all tissues and is activated upon binding to its ligands (IGF1, IGF2, insulin). Dysregulation of the IGF/IGF1R axis has been implicated in disorders of metabolism, growth and development, progression of cancers like lung and breast and even development of resistance to chemotherapy. Currently, this axis is a major target of research for chemotherapy and other metabolic disorders. However, pharmacological antagonists of IGF1R have failed to show significant benefit in overall patient population. One of the causes is that IGF1R expression and activity does not always correlate with disease progression and response to therapy. This highlights the crucial role of cellular and extracellular factors that modulate activity of IGF1R directly or indirectly. We have identified Ubiquilin1 as a novel interacting partner and regulator of IGF1R. Ubiquilins (UBQLN) are newly discovered proteins and are studied largely in the context of neurodegenerative disorders. Our laboratory recently showed that UBQLN1 is lost in about 50% of non‐small cell lung cancers, indicating a link between UBQLN1 expression and tumorigenesis. Hypothesis UBQLN1 regulates expression and activity of IGF1R. Methods We characterized regulation of IGF1R by UBQLN1 using the following methods – co‐immunoprecipitation, sub‐cellular fractionation, immunofluorescence, radioligand saturation binding, qRT‐PCR and Western Blot analyses. Results 1) UBQLN1 interacts with both phosphorylated and non‐phosphorylated IGF1R. 2) UBQLN1's primary association with IGF1R is through its chaperone‐like region (STI domains) and there exists a secondary association through its UBA (ubiquitin‐associated) domain, which leads to stabilization of IGF1R. 3) Following loss of UBQLN1 in lung adenocarcinoma cells, there is decreased expression of IGF1R at the mRNA and protein levels. 4) Fewer receptors are available for ligand binding on plasma membrane of UBQLN1 deficient cells. 5) The ratio of active: inactive (phosphorylated: non‐phosphorylated) IGF1R is significantly higher in cells that have loss of UBQLN1 expression. Conclusions We conclude that UBQLN1 is critical in normal regulation of IGF1R. Loss of UBQLN1 leads to persistent stimulation of IGF1R which may contribute to transforming events in UBQLN1 deficient cells. Understanding the role of UBQLN1 in regulating receptor tyrosine kinase activity can facilitate development of pharmacological drugs targeting novel pathways in cancers as well as metabolic diseases. Support or Funding Information R01CA193220