Secreted IGFBP5 mediates mTORC1-dependent feedback inhibition of IGF-1 signalling

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The PI(3)K-Akt-mTORC1 pathway is a highly dynamic network that is balanced and stabilized by a number of feedback inhibition loops1,2. Specifically, activation of mTORC1 has been shown to lead to the inhibition of its upstream growth factor signalling. Activation of the growth factor receptors is triggered by the binding of their cognate ligands in the extracellular space. However, whether secreted proteins contribute to the mTORC1-dependent feedback loops remains unclear. We found that cells with hyperactive mTORC1 secrete a protein that potently inhibits the function of IGF-1. Using a large-scale, unbiased quantitative proteomic platform, we comprehensively characterized the rapamycin-sensitive secretome in TSC2-/-mouse embryonic fibroblasts, and identified IGFBP5 as a secreted, mTORC1 downstream effector protein. IGFBP5 is a direct transcriptional target of HIF1, which itself is a known mTORC1 target3. IGFBP5 is a potent inhibitor of both the signalling and functional outputs of IGF-1. Once secreted, IGFBP5 cooperates with intracellular branches of the feedback mechanisms to block the activation of IGF-1 signalling. Finally, IGFBP5 is a potential tumour suppressor, and the proliferation of IGFBP5-mutated cancer cells is selectively blocked by IGF-1R inhibitors.

Original languageEnglish (US)
Pages (from-to)319-327
Number of pages9
JournalNature Cell Biology
Volume18
Issue number3
DOIs
StatePublished - Feb 25 2016

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Insulin-Like Growth Factor I
Proteins
Growth Factor Receptors
Extracellular Space
Sirolimus
Proteomics
mechanistic target of rapamycin complex 1
Neoplasms
Intercellular Signaling Peptides and Proteins
Fibroblasts
Ligands

ASJC Scopus subject areas

  • Cell Biology

Cite this

Secreted IGFBP5 mediates mTORC1-dependent feedback inhibition of IGF-1 signalling. / Ding, Ming; Bruick, Richard K.; Yu, Yonghao.

In: Nature Cell Biology, Vol. 18, No. 3, 25.02.2016, p. 319-327.

Research output: Contribution to journalArticle

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