title: 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.affiliation: Division of Rheumatology and Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Tamiko R
authors.initials: TR
authors.lastname: Katsumoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Kudo
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.forename: Aparna
authors.initials: A
authors.lastname: Sundaram
authors.forename: Elliott C
authors.initials: EC
authors.lastname: Callahan
authors.forename: Jing W
authors.initials: JW
authors.lastname: Zhu
authors.forename: Joseph
authors.initials: J
authors.lastname: Lin
authors.forename: Connor E
authors.initials: CE
authors.lastname: Rosen
authors.forename: Boryana N
authors.initials: BN
authors.lastname: Manz
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000473:pathology*; D001980:Bronchi / Q000473:pathology; D019070:Cell Lineage; D005260:Female; D017353:Gene Deletion; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D010047:Ovalbumin / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism; D015398:Signal Transduction; D014132:Trachea / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D010047:Ovalbumin; D019061:src-Family Kinases; C098066:Ptprj protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
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