The laminin receptor modulates granulocyte–macrophage colony-stimulating factor receptor complex formation and modulates its signaling
- Jian Chen*,†,
- Juan M. Cárcamo‡,
- Oriana Bórquez-Ojeda†,
- Hediye Erdjument-Bromage§,
- Paul Tempst§, and
- David W. Golde*,†,¶
- *Department of Pharmacology, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021; and †Program in Molecular Pharmacology and Chemistry, ‡Department of Clinical Laboratories, and §Molecular Biology Program, Memorial Sloan–Kettering Cancer Center, New York, NY 10021
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Edited by George F. Vande Woude, Van Andel Research Institute, Grand Rapids, MI, and approved September 23, 2003 (received for review July 21, 2003)
Abstract
Basement membrane matrix proteins are known to up-regulate granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling in neutrophils and mononuclear phagocytes, but the mechanisms involved are poorly understood. We used the intracellular portion of the α subunit of the GM-CSF receptor (αGMR) to search for interacting proteins and identified the 67-kDa laminin receptor (LR), a nonintegrin matrix protein receptor expressed in several types of host defense cells and certain tumors, as a binding partner. LR was found to interact with the β subunit of the GMR (βGMR) as well. Whereas GM-CSF functions by engaging the αGMR and βGMR into receptor complexes, LR inhibited GM-CSF-induced receptor complex formation. Laminin and fibronectin binding to LR was found to prevent the binding of βGMR to LR and relieved the LR inhibition of GMR. These findings provide a mechanistic basis for enhancing host defense cell responsiveness to GM-CSF at transendothelial migration sites while suppressing it in circulation.
Footnotes
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↵ ¶ To whom correspondence should be addressed. E-mail: d-golde{at}ski.mskcc.org.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: GM-CSF, granulocyte–macrophage colony-stimulating factor; LM, laminin; LR, LM receptor; GMR, GM-CSF receptor; FN, fibronectin; MAP, mitogen-activated protein; MAPK, MAP kinase; CBD, chitin-binding domain; TNF, tumor necrosis factor; HRP, horseradish peroxidase; ICD, intracellular domain; 8×GAS, 8 IFN-γ-activated site elements; Stat, signal transducer and activator of transcription.
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See Commentary on page 13737.
- Copyright © 2003, The National Academy of Sciences
