Research in the Rathmell Lab

It is critical that cell metabolism be closely linked to cellular energetic and biosynthetic demands. One of the most critical pathways vital to maintain cell function and survival is regulation of glucose metabolism. We have shown that increased glucose metabolism can both provide energy to cells and initiate pro-growth nutrient signaling pathways. Conversely, decreased glucose metabolism prevents lymphocyte proliferation and leads to cell death via Bcl-2 family proteins.

To address how glucose metabolism is regulated and how it affects cell fate, my laboratory focuses on glucose uptake and metabolism in lymphocytes. Lymphocytes are a dynamic model for cell changes in metabolism as resting cells use measurable, but low, amounts of glucose, but activated cells have orders or magnitude increases in glucose consumption.

Lymphocyte glucose metabolism is principally regulated by glucose uptake and the glucose transporter, Glut1. In the presence of cytokines or during immune responses, Glut1 expression is increased and Glut1 protein localizes to the cell surface. When cells are deprived stimulation, Glut1 mRNA levels decrease and Glut1 protein in internalized and degraded. Conversely, upregulation of Glut1 and glucose metabolism have long been observed in cancer cells of all varieties and this may play an important role in cancer cell growth and survival. It is largely unknown, however, how Glut1 expression or localization is regulated and how alterations in glucose uptake may affect immunity or cancer.

We have three related project areas in the lab to study this problem.

( 1 ) We are addressing how signaling pathways regulate Glut1 expression and trafficking. We have shown that cytokine-mediated activation of the kinase Akt1 is sufficient to promote Glut1 trafficking to the cell surface but does not affect Glut1 mRNA levels. We have also shown that a separate pathway to regulate Glut1 trafficking and degradation is regulated by Glut1 interacting proteins, such as GIPC. We are currently further defining the signaling pathways and mechanisms responsible for Glut1 expression and trafficking.

( 2 ) We have generated Glut1 transgenic mice that express Glut1 specifically in T cells to study the role of glucose uptake in T cell survival and activation. Thusfar, we have shown that increased glucose uptake promotes T cell hyperactivity and enhances T cell activation. Glucose uptake, therefore, is a limiting component of T cell activation. We are currently testing the hypothesis that the increased activity of Glut1 transgenic T cells may contribute to autoimmunity and that increased glucose uptake may contribute to disease.

( 3 ) We are also addressing the role of glucose uptake on cell death via regulation of the Bcl-2 family of proteins. We have found that the expression of the anti-apoptotic Bcl-2 family protein, Mcl-1, is affected by glucose uptake and hexokinase expression. We have now shown that increased glucose uptake initiates a signaling pathway leads to inhibitory phosphorylation of GSK-3 and stabilization of Mcl-1 protein. This pathway is likely to be activated in every cell type where Glut1 is induced, including stimulated lymphocytes and cancerous cells. We are currently studying the mechanisms and implications of this glucose-initiated cell signaling pathway in cell survival and function.

Our approach of studying the mechanism and role of metabolic regulation in lymphocytes bridges immunology and metabolism research. Lymphocytes are an excellent model system for metabolic research as they are highly sensitive to changes in nutrient uptake and must maintain the capacity to rapidly and strongly upregulate cellular metabolism in immune responses. By testing how changes in cell metabolism affect cell fate, we hope to address novel cell biological issues that affect lymphocyte survival, autoimmunity, and cancer.