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J Biol Chem. 2015 Feb 13;290(7):3894-909. doi: 10.1074/jbc.M114.614057. Epub 2014 Dec 23.

Protein-tyrosine phosphatase Shp2 positively regulates macrophage oxidative burst.

Author information

1
From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and xl9@iu.edu.
2
the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
3
the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
4
West Coast University, Los Angeles, California 91606.
5
From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, the Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany.
6
the Gunma University Graduate School of Health Sciences, Maebashi, Gunma 371-8514, Japan.
7
the Kobe University Graduate School of Medicine, Chuo-Ku, Kobe 650-0017, Japan, and.
8
the Department of Pathology, University of California, San Diego, La Jolla, California 92093.
9
From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, rchan@iu.edu.

Abstract

Macrophages are vital to innate immunity and express pattern recognition receptors and integrins for the rapid detection of invading pathogens. Stimulation of Dectin-1 and complement receptor 3 (CR3) activates Erk- and Akt-dependent production of reactive oxygen species (ROS). Shp2, a protein-tyrosine phosphatase encoded by Ptpn11, promotes activation of Ras-Erk and PI3K-Akt and is crucial for hematopoietic cell function; however, no studies have examined Shp2 function in particulate-stimulated ROS production. Maximal Dectin-1-stimulated ROS production corresponded kinetically to maximal Shp2 and Erk phosphorylation. Bone marrow-derived macrophages (BMMs) from mice with a conditionally deleted allele of Ptpn11 (Shp2(flox/flox);Mx1Cre+) produced significantly lower ROS levels compared with control BMMs. Although YFP-tagged phosphatase dead Shp2-C463A was strongly recruited to the early phagosome, its expression inhibited Dectin-1- and CR3-stimulated phospho-Erk and ROS levels, placing Shp2 phosphatase function and Erk activation upstream of ROS production. Further, BMMs expressing gain of function Shp2-D61Y or Shp2-E76K and peritoneal exudate macrophages from Shp2D61Y/+;Mx1Cre+ mice produced significantly elevated levels of Dectin-1- and CR3-stimulated ROS, which was reduced by pharmacologic inhibition of Erk. SIRPα (signal regulatory protein α) is a myeloid inhibitory immunoreceptor that requires tyrosine phosphorylation to exert its inhibitory effect. YFP-Shp2C463A-expressing cells have elevated phospho-SIRPα levels and an increased Shp2-SIRPα interaction compared with YFP-WT Shp2-expressing cells. Collectively, these findings indicate that Shp2 phosphatase function positively regulates Dectin-1- and CR3-stimulated ROS production in macrophages by dephosphorylating and thus mitigating the inhibitory function of SIRPα and by promoting Erk activation.

KEYWORDS:

Macrophage; NADPH Oxidase; Pattern Recognition Receptor (PRR); Phagocytosis; Tyrosine-Protein Phosphatase (Tyrosine Phosphatase)

PMID:
25538234
PMCID:
PMC4326800
DOI:
10.1074/jbc.M114.614057
[Indexed for MEDLINE]
Free PMC Article

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