Journal
GENOME BIOLOGY
Volume 8, Issue 7, Pages -Publisher
BMC
DOI: 10.1186/gb-2007-8-7-r142
Keywords
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Funding
- NATIONAL CANCER INSTITUTE [R33CA120732, R21CA120732] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM063702] Funding Source: NIH RePORTER
- NCI NIH HHS [R21 CA120732, CA120732, R33 CA120732] Funding Source: Medline
- NIGMS NIH HHS [R01 GM063702, GM063702] Funding Source: Medline
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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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