Research ArticleChemotaxis

The transmembrane adaptor protein NTAL limits mast cell chemotaxis toward prostaglandin E2

See allHide authors and affiliations

Sci. Signal.  13 Nov 2018:
Vol. 11, Issue 556, eaao4354
DOI: 10.1126/scisignal.aao4354

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Adapting to PGE2

The transmembrane adaptor proteins non–T cell activation linker (NTAL) and linker for activation of T cells (LAT) are structurally similar but nonredundant for immune cell function. Whereas LAT promotes mast cell degranulation in response to antibody-antigen complexes, NTAL inhibits this process. Halova et al. found that NTAL, but not LAT, inhibited the chemotaxis of mouse bone marrow–derived mast cells to the signaling lipid PGE2. NTAL reduced the phosphorylation of AKT and ezrin family proteins in PGE2-stimulated mast cells. Experiments with truncation and point mutants of NTAL indicated that C-terminal phosphorylation sites were critical for its inhibitory activity. These data suggest that NTAL not only inhibits mast cell degranulation after antigen stimulation but also limits mast cell migration in response to PGE2.

Abstract

Chemotaxis of mast cells is one of the crucial steps in their development and function. Non–T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2. Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate. In resting NTAL-deficient mast cells, phosphorylation of an inhibitory threonine in ERM family proteins accompanied increased activation of β1-containing integrins, which are features often associated with increased invasiveness in tumors. Rescue experiments indicated that only full-length, wild-type NTAL restored the chemotaxis of NTAL-deficient cells toward PGE2. Together, these data suggest that NTAL is a key inhibitor of mast cell chemotaxis toward PGE2, which may act through the RHOA/ERM/β1-integrin and PI3K/AKT axes.

View Full Text