| First Author | Wang X | Year | 2014 |
| Journal | Sci Signal | Volume | 7 |
| Issue | 337 | Pages | ra74 |
| PubMed ID | 25097034 | Mgi Jnum | J:259505 |
| Mgi Id | MGI:6141403 | Doi | 10.1126/scisignal.2005147 |
| Citation | Wang X, et al. (2014) Calmodulin and PI(3,4,5)P(3) cooperatively bind to the Itk pleckstrin homology domain to promote efficient calcium signaling and IL-17A production. Sci Signal 7(337):ra74 |
| abstractText | Precise regulation of the kinetics and magnitude of Ca(2+) signaling enables this signal to mediate diverse responses, such as cell migration, differentiation, vesicular trafficking, and cell death. We showed that the Ca(2+)-binding protein calmodulin (CaM) acted in a positive feedback loop to potentiate Ca(2+) signaling downstream of the Tec kinase family member Itk. Using NMR (nuclear magnetic resonance), we mapped CaM binding to two loops adjacent to the lipid-binding pocket within the Itk pleckstrin homology (PH) domain. The Itk PH domain bound synergistically to Ca(2+)/CaM and the lipid phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], such that binding to Ca(2+)/CaM enhanced the binding to PI(3,4,5)P3 and vice versa. Disruption of CaM binding attenuated Itk recruitment to the membrane and diminished release of Ca(2+) from the endoplasmic reticulum. Moreover, disruption of this feedback loop abrogated Itk-dependent production of the proinflammatory cytokine IL-17A (interleukin-17A) by CD4(+) T cells. Additionally, we found that CaM associated with PH domains from other proteins, indicating that CaM may regulate other PH domain-containing proteins. |
