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The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases
Tamiko R. Katsumoto, … , Dean Sheppard, Arthur Weiss
Tamiko R. Katsumoto, … , Dean Sheppard, Arthur Weiss
Published April 1, 2013
Citation Information: J Clin Invest. 2013;123(5):2037-2048. https://doi.org/10.1172/JCI66397.
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Research Article Pulmonology Article has an altmetric score of 8

The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases

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Abstract

Increased airway smooth muscle (ASM) contractility and the development of airway hyperresponsiveness (AHR) are cardinal features of asthma, but the signaling pathways that promote these changes are poorly understood. Tyrosine phosphorylation is tightly regulated by the opposing actions of protein tyrosine kinases and phosphatases, but little is known about whether tyrosine phosphatases influence AHR. Here, we demonstrate that genetic inactivation of receptor-like protein tyrosine phosphatase J (Ptprj), which encodes CD148, protected mice from the development of increased AHR in two different asthma models. Surprisingly, CD148 deficiency minimally affected the inflammatory response to allergen, but significantly altered baseline pulmonary resistance. Mice specifically lacking CD148 in smooth muscle had decreased AHR, and the frequency of calcium oscillations in CD148-deficient ASM was substantially attenuated, suggesting that signaling pathway alterations may underlie ASM contractility. Biochemical analysis of CD148-deficient ASM revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SRC family kinases (SFKs), implicating CD148 as a critical positive regulator of SFK signaling in ASM. The effect of CD148 deficiency on ASM contractility could be mimicked by treatment of both mouse trachea and human bronchi with specific SFK inhibitors. Our studies identify CD148 and the SFKs it regulates in ASM as potential targets for the treatment of AHR.

Authors

Tamiko R. Katsumoto, Makoto Kudo, Chun Chen, Aparna Sundaram, Elliott C. Callahan, Jing W. Zhu, Joseph Lin, Connor E. Rosen, Boryana N. Manz, Jae W. Lee, Michael A. Matthay, Xiaozhu Huang, Dean Sheppard, Arthur Weiss

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Figure 5

Deletion of CD148 on hematopoietic and endothelial cells does not attenuate AHR.

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Deletion of CD148 on hematopoietic and endothelial cells does not attenu...
(A) Flow cytometry plot showing deletion efficiency of CD148 gated on B220+ B cells of WT, WT Vav-Cre, PtprjTM–/TM–, and PtprjTM–fl/TM–;Vav-Cre mice. Mice of the indicated genotypes were immunized and intranasally challenged with OVA or saline (B–E). (B) Pulmonary resistance measurements after intravenous administration of increasing doses of ACh in control (WT), PtprjTM+/TM–, PtprjTM–fl/TM–, and PtprjTM–fl/TM–;Vav-Cre mice of the C57BL/6 strain. (C) BAL cell counts of total cells, macrophages, eosinophils, lymphocytes, and neutrophils of WT Vav-Cre, PtprjTM–fl/TM–, and PtprjTM–fl/TM–;Vav-Cre mice. (D) Histologic scoring by a blinded observer of H&E staining (left panel) and PAS staining of lung sections (right panel) in WT Vav-Cre, PtprjTM–fl/TM–, and PtprjTM–fl/TM–;Vav-Cre mice. (E) Relative OVA-specific serum IgE levels measured by ELISA in WT Vav-Cre, PtprjTM–fl/TM–, and PtprjTM–fl/TM–;Vav-Cre mice. Data for all panels show the means ± SEM, with 8 to 15 animals per group. *P < 0.05, 2-tailed Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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