Related Experiment Video

Updated: Mar 26, 2026

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice
08:09

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice

Published on: March 24, 2017

8.7K

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

Ming Ding1, Richard K Bruick1, Yonghao Yu1

  • 1Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235, USA.

Nature Cell Biology
|February 9, 2016
PubMed

Insights

Hyperactive mTORC1 signaling causes cells to secrete Insulin-like Growth Factor Binding Protein 5 (IGFBP5), which inhibits IGF-1 signaling. IGFBP5 acts as a tumor suppressor, and its mutation makes cancer cells sensitive to IGF-1R inhibitors.

Area of Science:

  • Cellular signaling pathways
  • Cancer biology
  • Proteomics

Background:

  • The PI(3)K-Akt-mTORC1 pathway is crucial for cell growth and survival.
  • mTORC1 activation can lead to feedback inhibition of upstream signaling.
  • The role of secreted proteins in mTORC1-dependent feedback loops is not well understood.

Purpose of the Study:

  • To investigate the contribution of secreted proteins to mTORC1-dependent feedback inhibition.
  • To identify secreted proteins regulated by mTORC1.
  • To characterize the function of these secreted proteins in regulating growth factor signaling.

Main Methods:

  • Utilized a large-scale, unbiased quantitative proteomic platform.
  • Analyzed the rapamycin-sensitive secretome in TSC2(-/-) mouse embryonic fibroblasts.
  • Investigated the transcriptional regulation of identified proteins by HIF1.
  • Assessed the inhibitory effects of identified proteins on IGF-1 signaling and function.

Main Results:

  • Identified Insulin-like Growth Factor Binding Protein 5 (IGFBP5) as a secreted, mTORC1-dependent effector protein.
  • Demonstrated that IGFBP5 is a direct transcriptional target of HIF1, itself an mTORC1 target.
  • Showed that secreted IGFBP5 potently inhibits both the signaling and functional outputs of IGF-1.
  • Confirmed that IGFBP5 cooperates with intracellular feedback mechanisms to block IGF-1 signaling activation.

Conclusions:

  • Hyperactive mTORC1 signaling leads to the secretion of IGFBP5, a novel feedback inhibitor of IGF-1.
  • IGFBP5 acts as a tumor suppressor, and its absence promotes cancer cell proliferation.
  • IGFBP5-mutated cancer cells exhibit selective sensitivity to IGF-1R inhibitors, suggesting therapeutic potential.

More Related Videos

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

14.8K
Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization08:57

Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization

Published on: October 6, 2019

10.9K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.1K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.7K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.9K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
3.0K
Hedgehog Signaling Pathway02:33

Hedgehog Signaling Pathway

The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
10.4K