PROJECT SUMMARY
Multicellular organisms develop receptor-mediated signal transduction initiated by extracellular growth factors to
proliferate. Insulin has long been known as a growth factor, and hyperinsulinemia can promote and sustain tumor
growth. Insulin receptor (IR) localizes to the cell surface plasma membrane both in metabolic tissue cells and in
highly proliferative cells such as immune cells and cancer cells. IR activates two downstream signaling pathways,
the PI3K-AKT pathway and the MAPK pathway, to regulate cell metabolism, proliferation, and growth. Despite
intriguing findings for IR signaling in systemic homeostasis, how the nutrient signaling maintains chromosome
stability still remains uncertain. This gap in our knowledge presents a key barrier to our understanding of the
function of insulin in cell proliferation and differentiation and its impact on human health, as hyperinsulinemia is
associated with various diseases including type 2 diabetes and cancer. Our goals are to explore the following
questions: (1) how does IR ensure accurate chromosome segregation in mitosis, and what is the physiological
function for IR in cell division; (2) how does IR selectively activate the PI3K-AKT vs. MAPK signaling branch; and
(3) what other factors are required for IR function in cell proliferation and differentiation? To reach our goals, we
are requesting an administrative supplement for microplate reader (CLARIOstar Plus, BMG Labtech). All projects
of our funded grant depend on this microplate reader. Until now, we have been borrowing time on a similar
microplate reader belonging to our colleague. Due to crowding on the machines, it is difficult to schedule time
slots, and there are restrictions on the use of the machine. The current shared microplate reader is more than
ten years old, and its sensitivity to fluorescence is low, requiring large amounts of reagents and limiting
applications. Collectively, the proposed research will advance our understanding of the function, regulation, and
mechanism(s) of insulin action in physiological cell proliferation and differentiation. Furthermore, our studies will
likely serve as a basis for further translational research and future therapeutics as hyperinsulinemia and type 2
diabetes are associated with increased risks for certain cancers and may also be harnessed for cancer
immunotherapies.