Btk regulation in human and mouse B cells via protein kinase C phosphorylation of IBtkγ

Elzbieta Janda, Camillo Palmieri, Antonio Pisano, Marilena Pontoriero, Enrico Iaccino, Cristina Falcone, Giuseppe Fiume, Marco Gaspari, Maria Nevolo, Emanuela Di Salle, Annalisa Rossi, Annamaria De Laurentiis, Adelaide Greco, Daniele Di Napoli, Elwin Verheij, Domenico Britti, Luca Lavecchia, Ileana Quinto, Giuseppe Scala

Research output: Contribution to journalArticlepeer-review


The inhibitor of Bruton tyrosine kinase γ (IBtkγ) is a negative regulator of the Bruton tyrosine kinase (Btk), which plays a major role in B-cell differentiation; however, the mechanisms of IBtkγ-mediated regulation of Btk are unknown. Here we report that B-cell receptor (BCR) triggering caused serine-phosphorylation of IBtkγ at protein kinase C consensus sites and dissociation from Btk. By liquid chromatography and mass-mass spectrometry and functional analysis, we identified IBtkγ-S87 and -S90 as the critical amino acid residues that regulate the IBtkγ binding affinity to Btk. Consistently, the mutants IBtkγ carrying S87A and S90A mutations bound constitutively to Btk and down-regulated Ca2+ fluxes and NF-κB activation on BCR triggering. Accordingly, spleen B cells from Ibtkγ-/- mice showed an increased activation of Btk, as evaluated by Y551-phosphorylation and sustained Ca2+ mobilization on BCR engagement. These findings identify a novel pathway of Btk regulation via protein kinase C phosphorylation of IBtkγ.

Original languageEnglish
Pages (from-to)6520-6531
Number of pages12
Issue number24
Publication statusPublished - Jun 16 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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