Nucleocytoplasmic shuttling of Bruton's tyrosine kinase

Bruton's tyrosine kinase (Btk), a nonreceptor cytoplasmic tyrosine kinase b elonging to the Tec family of kinases, has been shown to be critical for B cell proliferation, differentiation, and signaling. Loss-of-function mutati ons in the Btk gene lead to X-linked agammaglobulinemia (XLA), a primary im munodeficiency in humans, and the less severe condition xid in mice. Althou gh Btk is mainly localized in the cytoplasm under steady state conditions, it translocates to the plasma membrane upon growth factor stimulation and c rosslinking of the B cell receptor. Nevertheless, in ectopically as well as endogenously Btk-expressing cells, it can also translocate to the nucleus. Deletion of the pleckstrin homology (PH) domain (Delta PH1) leads, however , to an even redistribution of Btk within the nucleus and cytoplasm in the majority of transfected cells. In contrast, an SH3-deleted (Delta SH3) muta nt of Btk has been found to be predominantly nuclear. We also demonstrate t hat the nuclear accumulation of Delta PH1 is dependent on Src expression. T his nucleocytoplasmic shuttling is sensitive to the exportin 1/CRM1-inactiv ating drug, leptomycin B, indicating that Btk utilizes functional nuclear e xport signals. In addition, while the Delta PH1 mutant of Btk was found to be active and tyrosine-phosphorylated in vivo, Delta SH3 displayed decrease d autokinase activity and was not phosphorylated. Our findings indicate tha t the nucleocytoplasmic shuttling of Btk has implications regarding potenti al targets inside the nucleus, which may be critical in gene regulation dur ing B cell development and differentiation.