Format

Send to

Choose Destination
J Biol Chem. 2016 Apr 8;291(15):8140-9. doi: 10.1074/jbc.M115.693598. Epub 2016 Feb 10.

Regulation of Ligand and Shear Stress-induced Insulin-like Growth Factor 1 (IGF1) Signaling by the Integrin Pathway.

Author information

1
From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158.
2
Department of Pediatrics, University of California, San Francisco, California 94143.
3
Department of Pediatrics, Osaka University, Osaka, Japan 565-0871, and.
4
Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
5
From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158, Daniel.Bikle@ucsf.edu.

Abstract

Mechanical loading of the skeleton, as achieved during daily movement and exercise, preserves bone mass and stimulates bone formation, whereas skeletal unloading from prolonged immobilization leads to bone loss. A functional interplay between the insulin-like growth factor 1 receptor (IGF1R), a major player in skeletal development, and integrins, mechanosensors, is thought to regulate the anabolic response of osteogenic cells to mechanical load. The mechanistic basis for this cross-talk is unclear. Here we report that integrin signaling regulates activation of IGF1R and downstream targets in response to both IGF1 and a mechanical stimulus. In addition, integrins potentiate responsiveness of IGF1R to IGF1 and mechanical forces. We demonstrate that integrin-associated kinases, Rous sarcoma oncogene (SRC) and focal adhesion kinase (FAK), display distinct actions on IGF1 signaling; FAK regulates IGF1R activation and its downstream effectors, AKT and ERK, whereas SRC controls signaling downstream of IGF1R. These findings linked to our observation that IGF1 assembles the formation of a heterocomplex between IGF1R and integrin β3 subunit indicate that the regulation of IGF1 signaling by integrins proceeds by direct receptor-receptor interaction as a possible means to translate biomechanical forces into osteoanabolic signals.

KEYWORDS:

IGF1 receptor; IGF1 signaling; insulin-like growth factor (IGF); integrin; mechanotransduction; osteoblast; shear stress

PMID:
26865633
PMCID:
PMC4825016
DOI:
10.1074/jbc.M115.693598
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center