Type

Text

Type

Dissertation

Advisor

Zong, Wei-Xing. | Lin, Richard Z. | Brown, Deborah | Obeid, Lina | Girnun, Geoffrey.

Date

2017-08-01

Keywords

endocytosis | Cellular biology -- Molecular biology. | GLUT1 | metabolism | oncology | PI3K

Department

Department of Molecular and Cellular Biology.

Language

en_US

Source

This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree

Identifier

http://hdl.handle.net/11401/78120

Publisher

The Graduate School, Stony Brook University: Stony Brook, NY.

Format

application/pdf

Abstract

In multicellular organisms, nutrient uptake and metabolism are tightly regulated in response to growth factor availability through the trafficking of nutrient transporters. Oncogenic transformation is often associated with abnormal nutrient uptake and metabolism. Previous work demonstrated that Phosphoinositide 3-kinase (PI3K) p110? regulates intracellular membrane trafficking by modulating the small GTPase, Rab5. In this study, we used a SILAC mass spectrometry approach to identify plasma membrane proteins and novel endocytic cargos whose abundance is regulated by p110?. Among the peptides identified, the plasma membrane-associated glucose transporter, GLUT1, was increased in p110?-deficient cells, which correlated with increased uptake and metabolic processing of glucose, upregulation of growth signaling, and oncogenic transformation. Mechanistically, p110? functions as a positive regulator of endocytic turnover of GLUT1 via the tandem activation of two small GTPases, Rab5 and Rab7. Cells deficient in p110? failed to internalize and degrade GLUT1, thus promoting oncogenic metabolic reprogramming. p110?-silencing in lymphocytic pre-B-cells led to leukemic transformation in mice. Genetic ablation of p110? in hematopoietic progenitor cells (in the PTEN-null background) led to decreased myeloid leukemogenesis, yet enhanced transformation to lymphocytic malignancy. Consistent with these murine tumor models, we observed differential expression of p110? across various cancer types through mining of several human patient databases and identified a p110? ?tumor-associated mutation, which disrupts the p110? ?Rab5 interaction. These results indicate that p110? is an important regulator of bioenergetic homeostasis and by activating Rab5-mediated endocytic turnover of nutrient transporters, represses oncogenesis. | 107 pages

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