Regulation of insulin-like growth factor receptors by Ubiquilin1

Abstract

Insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase that mediates growth, proliferation and survival. Dysregulation of IGF pathway contributes to initiation, progression and metastasis of cancer and is also involved in diseases of glucose metabolism, such as Diabetes. We have identified Ubiquilin1 (UBQLN1) as a novel interaction partner of IGF1R, IGF2R and Insulin Receptor. UBQLN family of proteins have been studied primarily in the context of protein quality control and in the field of neurodegenerative disorders. Our laboratory discovered a link between UBQLN1 function and tumorigenesis, such that UBQLN1 is lost and under-expressed in 50% of human lung adenocarcinoma cases. We demonstrate here that UBQLN1 regulates expression and activity of IGF1R. Following loss of UBQLN1 in lung adenocarcinoma cells, there is accelerated loss of IGF1R. Despite decreased levels of total receptors, the ratio of active:total receptors is higher in cells that lack UBQLN1. UBQLN1 also regulates Insulin Receptor (INSR) and IGF2R post-stimulation with ligand. We conclude that UBQLN1 is essential for normal regulation of IGF receptors. UBQLN1 deficient cells demonstrate increased cell viability compared to control when serum starved and stimulation of IGF pathway in these cells increased their migratory potential by 3-fold. As the IGF pathway is involved in processes of normal growth, development, metabolism and cancer progression, understanding its regulation by Ubiquilin1 can be of tremendous value to many disciplines.

Ubiquilin proteins regulate EGFR levels and activity in lung adenocarcinoma cells

“…Additionally, we have reported dose and time dependent decreases in total IGF1R when stimulated with IGF ligand (Z. Kurlawala, Dunaway, et al, 2017). Likewise, in this study, lung adenocarcinoma cells lacking UBQLN1 also exhibit an enhanced degradation of EGFR when stimulated with EGF that is both dose and time dependent.…”

“…Our group is interested in understanding how loss of function of UBQLN proteins contributes to the metastatic progression of human lung adenocarcinoma.(Z. Kurlawala, Dunaway, et al, 2017; Shah et al, 2015; Yadav et al, 2017). Previously we have shown that interaction between UBQLN1 with IGF1R results in stabilization of this receptor.…”

“…siRNA transfections were performed as described previously(Z. Kurlawala, Dunaway, et al, 2017). 19 Briefly, 48 hours after transfection, cells were serum starved (SS) for 3 hours, incubated with protein synthesis inhibitor, Cycloheximide (CH, 10μM) for 1 hour prior to supplementing serum-free media with 25 or 50 ng/ml based on the experiment.…”

“…Kurlawala, Shah, et al, 2017) cell surface receptors, GABA-A (Saliba, Pangalos, & Moss, 2008), GPCR’s (E. N. N’Diaye et al, 2008), PSEN1/2 (Mah, Perry, Smith, & Monteiro, 2000; Massey et al, 2004), IGF1R (Z. Kurlawala, Dunaway, et al, 2017; Z. Kurlawala, Shah, et al, 2017), transcription factor regulators, IκBα (Feng et al, 2004) and other transmembrane proteins ESYT2 (Z.…”

“…Our lab was first to identify interaction of UBQLN1 with a RTK family member, namely insulin-like growth factor receptors (IGFRs) (Z. Kurlawala, Dunaway, et al, 2017). Loss of UBQLN1 leads to a significant decrease in the amount of total IGF1R, an increase in phosphorylated IGF1R and dramatic increases in their migratory potential when stimulated with IGF in lung adenocarcinoma.…”