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 (UBQLN) proteins are involved in diverse cellular processes like endoplasmic reticulum‐associated degradation, autophagy, apoptosis, and epithelial‐to‐mesenchymal transition. UBQLNs interact with a variety of substrates, including cell surface receptors, transcription factor regulators, proteasomal machinery proteins, and transmembrane proteins. In addition, previous work from our lab shows that UBQLN1 interacts with insulin‐like growth factor receptor family members (IGF1R, IGF2R, and INSR) and this interaction regulates the activity and proteostasis of IGFR family members. We wondered whether UBQLN proteins could also bind and regulate additional receptor tyrosine kinases. Thus, we investigated a link between UBQLN and the oncogene epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells. Loss of UBQLN1 occurs at high frequency in human lung cancer patient samples and we have shown that the loss of UBQLN1 is capable of altering processes involved in cell proliferation, migration, invasion, and epithelial‐to‐mesenchymal transition in lung adenocarcinoma cell lines. Here, we present data that loss of UBQLN1 resulted in increased turnover of total EGFR while increasing the relative amount of phosphorylated EGFR in lung adenocarcinoma cells, especially in the presence of its ligand EGF. Furthermore, the loss of UBQLN1 led to a more invasive cell phenotype as manifested by increased proliferation, migration, and speed of movement of these lung adenocarcinoma cells. Taken together, UBQLN1 regulates the expression and stability of EGFR in lung cancer cells.

19Ubiquilin proteins (UBQLNs) are involved in diverse cellular processes like ERAD 20 (endoplasmic reticulum associated degradation), autophagy, apoptosis and epithelial to 21 mesenchymal transition. UBQLNs interact with a variety of substrates, including cell 22 surface receptors, transcription factor regulators, proteasomal machinery proteins, and 23 transmembrane proteins. Additionally, previous work from our lab shows that UBQLN1 24 interacts with IGFR family members (IGF1R, IGF2R, INSR) and this interaction regulates 25 the activity and proteostasis of IGFR family members. Here, we examined regulation of 26 UBQLN1 with Epidermal Growth Factor Receptor (EGFR) in lung adenocarcinoma cells. 27 2 Loss of UBQLN1 occurs at high frequency in human lung cancer patient samples and we 28 have shown that loss of UBQLN1 is capable altering processes involved in cell 29 proliferation, migration, invasion and epithelial to mesenchymal transition in lung 30 adenocarcinoma cell lines. Here, we present data that loss of UBQLN1 resulted in 31 increased turnover of total EGFR, whilst increasing the relative amount of active EGFR 32 in lung adenocarcinoma cells, especially in the presence of its ligand EGF. Furthermore, 33 loss of UBQLN1 led to a more invasive cell phenotype as manifested by increased 34 proliferation, migration and speed of movement of these lung adenocarcinoma cells. 35Taken together, UBQLN1 regulates expression and stability of IGFRs and EGFR, 36 members of the receptor tyrosine kinase family of proteins in lung cancer cells. 37