# PI3 kinase PIK3CB (p110beta) in membrane trafficking and metabolism

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2020 · $354,563

## Abstract

PROJECT SUMMARY:
The Class IA phosphatidylinositol 3-kinases (PI3Ks) p110a and p110b isoforms are ubiquitously expressed
and respond to membrane receptor signals. They PI(3,4,5)P3, which acts as a signaling molecule to activate
downstream signaling pathways including the Akt/mTOR pathway. Despite their similarities, two isoforms have
distinct biochemical and biological features, one of which is that p110b has a kinase-independent function. We
have reported that p110b positively regulates the small GTPase Rab5 in a manner that is independent of its
catalytic activity. p110b, through a direct binding and as a molecular scaffold, keeps Rab5 in its “active” GTP-
bound form by preventing Rab5 from interacting with its GTPase-activating protein (GAP), which inactivates
Rab5 by hydrolyzing its GTP to GDP. Rab5 is well known for regulating endocytosis. Our preliminary data
strongly indicate that p110b can regulate endocytic turnover of cell surface nutrient transporters such as
glucose transporter 1 (GLUT1) in response to growth factor deprivation. We found that genetic ablation or
shRNA silencing of p110b decreased the level of Rab5-GTP. This resulted in increased cell surface GLUT1
that led to increased glucose utilization of cell lines and promoted their oncogenic transformation. These
findings lead us to propose the hypothesis that p110b, as a molecular scaffold, activates Rab5 and endocytic
turnover of nutrient transporters. We further propose that this novel function of p110b regulates membrane
trafficking and cell metabolism and homeostasis. We have designed two Specific Aims to test this hypothesis
and establish its biological relevance. Aim 1: Test the hypothesis that p110b facilitates Rab5-mediated
endocytic turnover of nutrient transporters. We will use FL5.12, MEFs, HK-2, and MCF10A cells to determine
that p110b deficiency can lead to the stabilization of nutrient transporters, and to determine if the failure of
endocytic turnover is the result of Rab5 inactivation. Aim 2. Determine the molecular and cell biological
consequence of the stabilized nutrient transporters in p110b-deficient cells (with a focus on GLUT1). We will
characterize the metabolic features associated with the nutrient transporter stabilization, and characterize the
growth/proliferation signaling in p110b-deficient cells. We will also determine the physiological effects of the
p110b-Rab5 interaction in vivo.
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## Key facts

- **NIH application ID:** 10001471
- **Project number:** 5R01CA232246-03
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Wei-Xing Zong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,563
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001471

## Citation

> US National Institutes of Health, RePORTER application 10001471, PI3 kinase PIK3CB (p110beta) in membrane trafficking and metabolism (5R01CA232246-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10001471. Licensed CC0.

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