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

The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases

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 8

Inhibition of SRC family kinases recapitulates CD148 deficiency and leads to impaired contractility of mouse tracheal rings and human bronchial rings.

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Inhibition of SRC family kinases recapitulates CD148 deficiency and lead...
Mouse tracheal rings were isolated and pretreated with the specific SRC family kinase inhibitor SU6656 at 10 μM for 12 hours prior to stimulation with MCh (A), and contractile force measurements were made with a force transducer. Mouse tracheal rings from WT (B) or PtprjTM–/TM– (C) mice were isolated and pretreated with the specific SRC family kinase inhibitor AZD0530 at 5 μM for 12 hours prior to stimulation with MCh. *P < 0.05, 2-way ANOVA. (D) Human bronchial rings isolated from an explanted human lung were pretreated with SU6656 at 10 μM or vehicle for 1 hour prior to stimulation with MCh and contractile force was measured. Data are the means ± SEM for 5 to 6 mouse tracheal rings (A–C) and 6 human bronchial rings (D) per condition. **P < 0.01, ***P < 0.001, 2-way ANOVA.