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Title: A NPxY-independent {beta}5 integrin activation signal regulates phagocytosis of apoptotic cells

Abstract

Integrin receptors are heterodimeric transmembrane receptors with critical functions in cell adhesion and migration, cell cycle progression, differentiation, apoptosis, and phagocytosis of apoptotic cells. Integrins are activated by intracellular signaling that alter the binding affinity for extracellular ligands, so-called inside to outside signaling. A common element for integrin activation involves binding of the cytoskeletal protein talin, via its FERM domain, to a highly conserved NPxY motif in the {beta} chain cytoplasmic tails, which is involved in long-range conformation changes to the extracellular domain that impinges on ligand affinity. When the human beta-5 ({beta}5) integrin cDNA was expressed in {alpha}v positive, {beta}5 and {beta}3 negative hamster CS-1 cells, it promoted NPxY-dependent adhesion to VTN-coated surfaces, phosphorylation of FAK, and concomitantly, {beta}5 integrin-EGFP protein was recruited into talin and paxillin-containing focal adhesions. Expression of a NPxY destabilizing {beta}5 mutant (Y750A) abrogated adhesion and {beta}5-Y750A-EGFP was excluded from focal adhesions at the tips of stress fibers. Surprisingly, expression of {beta}5 Y750A integrin had a potent gain-of-function effect on apoptotic cell phagocytosis, and further, a {beta}5-Y750A-EGFP fusion integrin readily bound MFG-E8-coated 10 {mu}m diameter microspheres developed as apoptotic cell mimetics. The critical sequences in {beta}5 integrin were mapped to a YEMAS motif just proximalmore » to the NPxY motif. Our studies suggest that the phagocytic function of {beta}5 integrin is regulated by an unconventional NPxY-talin-independent activation signal and argue for the existence of molecular switches in the {beta}5 cytoplasmic tail for adhesion and phagocytosis.« less

Authors:
;  [1];  [1]
  1. Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103-6399 (United States)
Publication Date:
OSTI Identifier:
21033017
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 364; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2007.10.049; PII: S0006-291X(07)02189-4; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CELL CYCLE; FIBERS; HAMSTERS; LIGANDS; MICROSPHERES; MUTANTS; PHAGOCYTOSIS; PHOSPHORYLATION; RECEPTORS

Citation Formats

Singh, Sukhwinder, D'mello, Veera, Henegouwen, Paul van Bergen en, Birge, Raymond B, and Utrecht University, Department of Molecular Cell Biology, Padualaan 8 3584 CH Utrecht. A NPxY-independent {beta}5 integrin activation signal regulates phagocytosis of apoptotic cells. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.10.049.
Singh, Sukhwinder, D'mello, Veera, Henegouwen, Paul van Bergen en, Birge, Raymond B, & Utrecht University, Department of Molecular Cell Biology, Padualaan 8 3584 CH Utrecht. A NPxY-independent {beta}5 integrin activation signal regulates phagocytosis of apoptotic cells. United States. doi:10.1016/j.bbrc.2007.10.049.
Singh, Sukhwinder, D'mello, Veera, Henegouwen, Paul van Bergen en, Birge, Raymond B, and Utrecht University, Department of Molecular Cell Biology, Padualaan 8 3584 CH Utrecht. Fri . "A NPxY-independent {beta}5 integrin activation signal regulates phagocytosis of apoptotic cells". United States. doi:10.1016/j.bbrc.2007.10.049.
@article{osti_21033017,
title = {A NPxY-independent {beta}5 integrin activation signal regulates phagocytosis of apoptotic cells},
author = {Singh, Sukhwinder and D'mello, Veera and Henegouwen, Paul van Bergen en and Birge, Raymond B and Utrecht University, Department of Molecular Cell Biology, Padualaan 8 3584 CH Utrecht},
abstractNote = {Integrin receptors are heterodimeric transmembrane receptors with critical functions in cell adhesion and migration, cell cycle progression, differentiation, apoptosis, and phagocytosis of apoptotic cells. Integrins are activated by intracellular signaling that alter the binding affinity for extracellular ligands, so-called inside to outside signaling. A common element for integrin activation involves binding of the cytoskeletal protein talin, via its FERM domain, to a highly conserved NPxY motif in the {beta} chain cytoplasmic tails, which is involved in long-range conformation changes to the extracellular domain that impinges on ligand affinity. When the human beta-5 ({beta}5) integrin cDNA was expressed in {alpha}v positive, {beta}5 and {beta}3 negative hamster CS-1 cells, it promoted NPxY-dependent adhesion to VTN-coated surfaces, phosphorylation of FAK, and concomitantly, {beta}5 integrin-EGFP protein was recruited into talin and paxillin-containing focal adhesions. Expression of a NPxY destabilizing {beta}5 mutant (Y750A) abrogated adhesion and {beta}5-Y750A-EGFP was excluded from focal adhesions at the tips of stress fibers. Surprisingly, expression of {beta}5 Y750A integrin had a potent gain-of-function effect on apoptotic cell phagocytosis, and further, a {beta}5-Y750A-EGFP fusion integrin readily bound MFG-E8-coated 10 {mu}m diameter microspheres developed as apoptotic cell mimetics. The critical sequences in {beta}5 integrin were mapped to a YEMAS motif just proximal to the NPxY motif. Our studies suggest that the phagocytic function of {beta}5 integrin is regulated by an unconventional NPxY-talin-independent activation signal and argue for the existence of molecular switches in the {beta}5 cytoplasmic tail for adhesion and phagocytosis.},
doi = {10.1016/j.bbrc.2007.10.049},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 364,
place = {United States},
year = {2007},
month = {12}
}