Transmembrane adaptor protein PAG/CBP is involved in both positive and negative regulation of mast cell signaling

Lubica Draberova, Viktor Bugajev, Lucie Potuckova, Ivana Halova, Monika Bambouskova, Iva Polakovicova, Ramnik J. Xavier, Brian Seed, Petr Drabera

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The transmembrane adaptor protein PAG/CBP (here, PAG) is expressed in multiple cell types. Tyrosine-phosphorylated PAG serves as an anchor for C-terminal SRC kinase, an inhibitor of SRC-family kinases. The role of PAG as a negative regulator of immunoreceptor signaling has been examined in several model systems, but no functions in vivo have been determined. Here, we examined the activation of bone marrow-derived mast cells (BMMCs) with PAG knockout and PAG knockdown and the corresponding controls. Our data show that PAG-deficient BMMCs exhibit impaired antigen-induced degranulation, extracellular calcium uptake, tyrosine phosphorylation of several key signaling proteins (including the high-affinity IgE receptor subunits, spleen tyrosine kinase, and phospholipase C), production of several cytokines and chemokines, and chemotaxis. The enzymatic activities of the LYN and FYN kinases were increased in nonactivated cells, suggesting the involvement of a LYN- and/or a FYNdependent negative regulatory loop. When BMMCs from PAG-knockout mice were activated via the KIT receptor, enhanced degranulation and tyrosine phosphorylation of the receptor were observed. In vivo experiments showed that PAG is a positive regulator of passive systemic anaphylaxis. The combined data indicate that PAG can function as both a positive and a negative regulator of mast cell signaling, depending upon the signaling pathway involved.

Original languageEnglish
Pages (from-to)4285-4300
Number of pages16
JournalMolecular and cellular biology
Volume34
Issue number23
DOIs
StatePublished - 2014

Fingerprint

Dive into the research topics of 'Transmembrane adaptor protein PAG/CBP is involved in both positive and negative regulation of mast cell signaling'. Together they form a unique fingerprint.

Cite this