title: Regulation of Ligand and Shear Stress-induced Insulin-like Growth Factor 1 (IGF1) Signaling by the Integrin Pathway.
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.
authors: From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158.
authors: Candice G T
authors: CG
authors: Tahimic
authors: Department of Pediatrics, University of California, San Francisco, California 94143.
authors: Roger K
authors: RK
authors: Long
authors: Department of Pediatrics, Osaka University, Osaka, Japan 565-0871, and.
authors: Takuo
authors: T
authors: Kubota
authors: From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158.
authors: Maggie Yige
authors: MY
authors: Sun
authors: From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158.
authors: Hashem
authors: H
authors: Elalieh
authors: From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158.
authors: Chak
authors: C
authors: Fong
authors: From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158.
authors: Alicia T
authors: AT
authors: Menendez
authors: From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158.
authors: Yongmei
authors: Y
authors: Wang
authors: Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Jean-Pierre
authors: JP
authors: Vilardaga
authors: From the Endocrine Research Unit, Veterans Affairs Medical Center, San Francisco, California 94121, University of California, San Francisco, California 94158, Daniel.Bikle@ucsf.edu.
authors: Daniel D
authors: DD
authors: Bikle
mesh_terms: D002460:Cell Line; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D016023:Integrins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
keywords: IGF1 receptor; IGF1 signaling; insulin-like growth factor (IGF); integrin; mechanotransduction; osteoblast; shear stress