Nucleocytoplasmic Shuttling of Bruton's Tyrosine Kinase

• Published in: The Journal of biological chemistry 2000-12, Vol.275 (51), p.40614-40619
• Main Authors: Mohamed, Abdalla J., Vargas, Leonardo, Nore, Beston F., Bäckesjö, Carl-Magnus, Christensson, Birger, Smith, C.I. Edvard
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Cell Nucleus - enzymology; Cytoplasm - enzymology; Green Fluorescent Proteins; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Medicin och hälsovetenskap; Phosphorylation; Protein Transport; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M006952200

Bruton's tyrosine kinase (Btk), a nonreceptor cytoplasmic tyrosine kinase belonging to the Tec family of kinases, has been shown to be critical for B cell proliferation, differentiation, and signaling. Loss-of-function mutations in the Btk gene lead to X-linked agammaglobulinemia (XLA), a primary immunodeficiency in humans, and the less severe condition xid in mice. Although Btk is mainly localized in the cytoplasm under steady state conditions, it translocates to the plasma membrane upon growth factor stimulation and cross-linking 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 (ΔPH1) leads, however, to an even redistribution of Btk within the nucleus and cytoplasm in the majority of transfected cells. In contrast, an SH3-deleted (ΔSH3) mutant of Btk has been found to be predominantly nuclear. We also demonstrate that the nuclear accumulation of ΔPH1 is dependent on Src expression. This nucleocytoplasmic shuttling is sensitive to the exportin 1/CRM1-inactivating drug, leptomycin B, indicating that Btk utilizes functional nuclear export signals. In addition, while the ΔPH1 mutant of Btk was found to be active and tyrosine-phosphorylated in vivo, ΔSH3 displayed decreased autokinase activity and was not phosphorylated. Our findings indicate that the nucleocytoplasmic shuttling of Btk has implications regarding potential targets inside the nucleus, which may be critical in gene regulation during B cell development and differentiation.