SiRNA Screen of the Human Signaling Proteome Identifies the PtdIns(3,4,5)P3-mTOR Signaling Pathway As a Primary Regulator of Transferrin Uptake

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2007 Jul 21

PMID 17640392

Citations 34

Authors

Thierry Galvez

Mary N Teruel

Won Do Heo

Joshua T Jones

Man Lyang Kim

Jen Liou

Jason W Myers

Tobias Meyer

Affiliations

Soon will be listed here.

Abstract

Background: Iron uptake via endocytosis of iron-transferrin-transferrin receptor complexes is a rate-limiting step for cell growth, viability and proliferation in tumor cells as well as non-transformed cells such as activated lymphocytes. Signaling pathways that regulate transferrin uptake have not yet been identified.

Results: We surveyed the human signaling proteome for regulators that increase or decrease transferrin uptake by screening 1,804 dicer-generated signaling small interfering RNAs using automated quantitative imaging. In addition to known transport proteins, we identified 11 signaling proteins that included a striking signature set for the phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3)-target of rapamycin (mTOR) signaling pathway. We show that the PI3K-mTOR signaling pathway is a positive regulator of transferrin uptake that increases the number of transferrin receptors per endocytic vesicle without affecting endocytosis or recycling rates.

Conclusion: Our study identifies the PtdIns(3,4,5)P3-mTOR signaling pathway as a new regulator of iron-transferrin uptake and serves as a proof-of-concept that targeted RNA interference screens of the signaling proteome provide a powerful and unbiased approach to discover or rank signaling pathways that regulate a particular cell function.

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