| First Author | Simonowski A | Year | 2020 |
| Journal | Biochim Biophys Acta Mol Cell Res | Volume | 1867 |
| Issue | 4 | Pages | 118622 |
| PubMed ID | 31837347 | Mgi Jnum | J:287915 |
| Mgi Id | MGI:6390352 | Doi | 10.1016/j.bbamcr.2019.118622 |
| Citation | Simonowski A, et al. (2020) Differential use of BTK and PLC in FcepsilonRI- and KIT-mediated mast cell activation: A marginal role of BTK upon KIT activation. Biochim Biophys Acta Mol Cell Res 1867(4):118622 |
| abstractText | In mast cells (MCs), the TEC family kinase (TFK) BTK constitutes a central regulator of antigen (Ag)-triggered, FcepsilonRI-mediated PLCgamma phosphorylation, Ca(2+) mobilization, degranulation, and pro-inflammatory cytokine production. Less is known about the function of BTK in the context of stem cell factor (SCF)-induced KIT signaling. In bone marrow-derived MCs (BMMCs), Ag stimulation caused intense phosphorylation of BTK at Y551 in its active center and at Y223 in its SH3-domain, whereas in response to SCF only Y223 was significantly phosphorylated. Further data using the TFK inhibitor Ibrutinib indicated that BTK Y223 is phosphorylated by a non-BTK TFK upon SCF stimulation. In line, SCF-induced PLCgamma1 phosphorylation was stronger attenuated by Ibrutinib than by BTK deficiency. Subsequent pharmacological analysis of PLCgamma function revealed a total block of SCF-induced Ca(2+) mobilization by PLC inhibition, whereas only the sustained phase of Ca(2+) flux was curtailed in Ag-stimulated BMMCs. Despite this severe stimulus-dependent difference in inducing Ca(2+) mobilization, PLCgamma inhibition suppressed Ag- and SCF-induced degranulation and pro-inflammatory cytokine production to comparable extents, suggesting involvement of additional TFK(s) or PLCgamma-dependent signaling components. In addition to PLCgamma, the MAPKs p38 and JNK were activated by Ag in a BTK-dependent manner; this was not observed upon SCF stimulation. Hence, FcepsilonRI and KIT employ different mechanisms for activating PLCgamma, p38, and JNK, which might strengthen their cooperation regarding pro-inflammatory MC effector functions. Importantly, our data clearly demonstrate that analyzing BTK Y223 phosphorylation is not sufficient to prove BTK activation. |
