Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain.
Bruton's agammaglobulinemia tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase important in B-lymphocyte development, differentiation, and signaling. Btk is a member of the Tec family of kinases. Mutations in the Btk gene lead to X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Activation of Btk triggers a cascade of signaling events that culminates in the generation of calcium mobilization and fluxes, cytoskeletal rearrangements, and transcriptional regulation involving nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells (NFAT). In B cells, NF-kappaB was shown to bind to the Btk promoter and induce transcription, whereas the B-cell receptor-dependent NF-kappaB signaling pathway requires functional Btk. Moreover, Btk activation is tightly regulated by a plethora of other signaling proteins including protein kinase C (PKC), Sab/SH3BP5, and caveolin-1. For example, the prolyl isomerase Pin1 negatively regulates Btk by decreasing tyrosine phosphorylation and steady state levels of Btk. It is intriguing that PKC and Pin1, both of which are negative regulators, bind to the pleckstrin homology domain of Btk. To this end, we describe here novel mutations in the pleckstrin homology domain investigated for their transforming capacity. In particular, we show that the mutant D43R behaves similar to E41K, already known to possess such activity.
Mohamed
Abdalla J
AJ
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden.
Yu
Liang
L
Bäckesjö
Carl-Magnus
CM
Vargas
Leonardo
L
Faryal
Rani
R
Aints
Alar
A
Christensson
Birger
B
Berglöf
Anna
A
Vihinen
Mauno
M
Nore
Beston F
BF
Smith
C I Edvard
CI
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000276:immunology; D000818:Animals; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D053632:X-Linked Combined Immunodeficiency Diseases / Q000276:immunology
D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse