Abstract
The cellular repressor of E1A-stimulated genes (CREG) is a 220 amino acid glycoprotein structurally similar to oxidoreductases. However, CREG does not have enzymatic activities because it cannot bind to the cofactor flavin mononucleotide. Although CREG can be secreted, it is mainly an intracellular protein localized in the endocytic-lysosomal compartment. It undergoes proteolytic maturation mediated by lysosomal cysteine proteases. Biochemical studies have demonstrated that CREG interacts with mannose-6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R) and exocyst Sec8. CREG inhibits proliferation and induces differentiation and senescence when overexpressed in cultured cells. In Drosophila, RNAi-mediated knockdown of CREG causes developmental lethality at the pupal stage. In mice, global deletion of the CREG1 gene leads to early embryonic death. These findings establish an essential role for CREG in development. CREG1 haploinsufficient and liver-specific knockout mice are susceptible to high fat diet-induced obesity, hepatic steatosis and insulin resistance. The purpose of this review is to provide an overview of what we know about the biochemistry and biology of CREG and to discuss the important questions that remain to be addressed in the future.
Highlights
The adenovirus E1A protein promotes cellular proliferation and inhibits differentiation through its interaction with many cellular proteins including retinoblastoma (Chakraborty and Tansey, 2009). Veal et al (1998) identified human cellular repressor of E1A-stimulated genes (CREG) in yeast two-hybrid screening of a Drosophila cDNA library
Cell culture studies demonstrated a role for CREG1 in growth, differentiation and senescence
The endosomal-lysosomal system has been shown to play an important signaling role in the activation and degradation of signaling molecules (Dobrowolski and De Robertis, 2011; SunWada and Wada, 2015; Bergeron et al, 2016; Bakker et al, 2017). It controls the activation of the mechanistic target of rapamycin complex 1 (Huber and Teis, 2016; Lim and Zoncu, 2016; Perera and Zoncu, 2016)
Summary
CREG can be secreted, it is mainly an intracellular protein localized in the endocyticlysosomal compartment. It undergoes proteolytic maturation mediated by lysosomal cysteine proteases. Biochemical studies have demonstrated that CREG interacts with mannose-6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R) and exocyst Sec. In Drosophila, RNAi-mediated knockdown of CREG causes developmental lethality at the pupal stage. Global deletion of the CREG1 gene leads to early embryonic death. These findings establish an essential role for CREG in development. CREG1 haploinsufficient and liver-specific knockout mice are susceptible to high fat diet-induced obesity, hepatic steatosis and insulin resistance.
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