SLC2A9, A Candidate ER GLUT in Normal and Cancer Cells

Washington University, Saint Louis MO

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Abstract

DESCRIPTION: (Scanned from the applicant's description) Glucose is the preferred energy substrate of normal and malignant tissues. Adequate circulating levels are maintained by dietary intake, glycogenolysis and gluconeogenesis in the liver and kidney. Several plasma membrane glucose transporter proteins have been described, however a microsomal glucose transporter, which may be required for transport of glucose from the endoplasmic reticulum in the final step of glycogenolysis and gluconeogenesis, has not been found. We cloned a novel member of the human glucose transporter family from human sarcoma and kidney cDNA (HGMW-approved symbol is SLC2A9 (GLUT9), GenBank accession No. AF210317). This cDNA encodes a protein that is 540 amino acids in length, and has 12 putative membrane-spanning domains. The predicted protein sequence has 44 percent and 38 percent sequence identity to Glut 5 and Glut 1, respectively. The cDNA is expressed primarily in human liver and kidney, and has a possible NH2 terminal endoplasmic reticulum targeting motif. It is also expressed in human colon cancer and soft tissue sarcomas. We hypothesize that SLC2A9 is the endoplasmic reticulum (ER) glucose transporter (also called T3) which is associated with the microsomal Glucose-6-phosphatase (G6Pase) complex. Accordingly, we will: Demonstrate the sub-cellular localization of SLC2A9 in normal and malignant cells. Determine the function of SLC2A9 by expression in a Xenopus oocyte expression system, and Evaluate the phenotypic and biochemical features of an SLC2A9 null mouse. If SLC2A9 is the ER glucose transporter of the G6Pase system, we predict that the null mouse will demonstrate features of glycogen storage disease (GSD), as reported in the G6Pase (-/-) mouse. Identification of SLC2A9 as the endoplasmic reticulum glucose transporter will improve understanding of GSDs, and of glucose metabolism in benign and malignant tissues.