siRNA screen of the human signaling proteome identifies the PtdIns(3,4,5)P3-mTOR signaling pathway as a primary regulator of transferrin uptake. Academic Article uri icon

Overview

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.

publication date

  • January 1, 2007

Research

keywords

  • Phosphatidylinositol Phosphates
  • Protein Kinases
  • Proteome
  • Proteomics
  • Transferrin

Identity

PubMed Central ID

  • PMC2323231

Scopus Document Identifier

  • 39749108111

Digital Object Identifier (DOI)

  • 10.1093/nar/gki069

PubMed ID

  • 17640392

Additional Document Info

volume

  • 8

issue

  • 7