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Biochem J. 2017 Dec 6;474(24):4105-4118. doi: 10.1042/BCJ20170620.

Regulation of insulin-like growth factor receptors by Ubiquilin1.

Kurlawala Z1,2,3, Dunaway R1, Shah PP1,2,3, Gosney JA1,2,3, Siskind LJ1,2,3, Ceresa BP1,2,3, Beverly LJ4,2,3.

Author information

1
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville KY, U.S.A.
2
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, U.S.A.
3
Division of Hematology and Oncology, School of Medicine, University of Louisville, Louisville, KY, U.S.A.
4
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville KY, U.S.A. levi.beverly@louisville.edu.

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 the 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 (INSR). 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 underexpressed in 50% of human lung adenocarcinoma cases. We demonstrate here that UBQLN1 regulates the 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 INSR and IGF2R post-stimulation with ligand. We conclude that UBQLN1 is essential for normal regulation of IGF receptors. UBQLN-1-deficient cells demonstrate increased cell viability compared with 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.

KEYWORDS:

Ubiquilin; insulin-like growth factor; receptor tyrosine kinases; trafficking; turnover

PMID:
29054976
PMCID:
PMC5842694
DOI:
10.1042/BCJ20170620
[Indexed for MEDLINE]
Free PMC Article

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