BTK (Bruton agammaglobulinemia tyrosine kinase)

2008-03-01   Rudi W Hendriks , Pieter Fokko van Loo 

Department of Pulmonary Medicine, Room Ee2251a, Erasmus MC Rotterdam, PO Box 2040 NL 3000 CA Rotterdam, The Netherlands

Identity

HGNC
LOCATION
Xq22.1
LOCUSID
ALIAS
AGMX1,AT,ATK,BPK,IMD1,MGC126261,MGC126262,PSCTK1,XLA
FUSION GENES

DNA/RNA

Description

The gene spans over 36 kb and is composed of 19 exons, both in human and mouse.

Transcription

The transcript is about 2,573 bps in human and about 2,477 bps mice and has UTR regions in exons 1, 2 and 19.

Proteins

Atlas Image
Table 1: BTK dependent receptor signaling cascades.

Description

The BTK protein is a 77 kDa protein of 659 amino acids. Translation of the BTK transcript starts at the ATG site that is located in exon 2 and ends in exon 19.
The BTK protein is composed of an N-terminal Pleckstrin homology (PH) domain followed three protein interacting domains: Tec homology (TH) region, Src homology 3 (SH3) domain and SH2 domain. A tyrosine-kinase catalytic domain is located at the C-terminal end. Two tyrosine phosphorylation sites are located at the positions Y223 and Y551, which are located in the SH3 and kinase domain, respectively. Both phosphorylation sites play a pivotal role in the activation of BTK. Y551 is transphosphorylated by Syk (or Lyn) kinases which promotes the catalytic activity of BTK, with subsequent autophosphorylation at position Y223.

Expression

BTK is expressed in all cell lineages of the hematopoietic system, except for T cells. Therefore BTK expression is found in B lymphocytes, platelets, erythroid and myeloid cells (monocytes, macrophages, granulocytes and dendritic cells). Within the B cell lineage, BTK is already expressed in the earliest detectable B cell precursors, and expression is downregulated in plasma cells.

Localisation

The protein is predominantly localized in the cytoplasm. BTK activation upon receptor signaling results in translocation of BTK protein from the cytoplasm to the membrane. The membrane association of BTK is dependent on the interaction of its PH domain with PIP3 (phosphatidylinositol (3,4,5)-trisphosphate), which is a second messenger that is synthesized from PIP2 by PI3K (phosphoinositide-3 kinase). The translocation to the membrane brings the BTK protein in close proximity to the Lyn en Syk kinases that transphosphorylate BTK at tyrosine Y551. The E41K gain-of-function BTK mutant, in which the E41 residue is mutated in to a lysine residue, manifests increased membrane localization in quiescent cells, independent of PI3K activity, probably resulting from increased affinity for PIP2. Transforming activity is kinase-domain dependent and is potentiated by introduction of a second mutation at position Y223.

Function

BTK is a signaling mediator downstream of a variety of receptors in several different cell types (listed in Table 1), including the B cell receptor (BCR).

Homology

BTK belongs to the TEC family of cytoplasmic tyrosine kinases. This family is composed of TEC, BTK, TXK/RLK, ITK/EMT, and BMX. Btk is highly conserved between mouse and human.

Implicated in

Entity name
Pre-B cell tumors
Note
Truncated BTK forms in human BCR-ABL1 + leukemia
BTK is constitutively phosphorylated by the oncogenic BCR- ABL1 fusion product. Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1+ leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself. BCR-ABL1 cannot directly bind to full-length BTK, but induces the expression of a truncated BTK splice variant that acts as a linker between the two kinases. Thus, truncated BTK enables BCR-ABL1-dependent activation of full-length BTK, which initiates downstream survival signals and mimics pre-B cell receptor signaling.
Defective expression of BTK in acute lymphoblastic leukemia (ALL)
In an analysis of BTK protein and mRNA expression in infant B-lineage leukemia cells variable but often reduced levels of BTK expression was found. RT-PCR revealed the presence of aberrant transcripts which would encode BTK proteins with either a deleted or a truncated kinase domain. In infant pre-B MLL-AF4+ leukemia cells full-length BTK was detectable in only half of the cases, whereas in ALL cells harboring other fusion genes (including BCR-ABL1, E2A- PBX1 and TEL- AML1) full-length BTK was typically co-expressed with kinase-deficient variants. Thus, lack of BTK or expression of dominant-negative BTK splice variants in B cell precursor leukemia cells can inhibit differentiation beyond the pre-B cell stage and protect from radiation-induced apoptosis.
Btk as a tumor suppressor in pre-B cell leukemia in mice
Expression of the pre-B cell receptor (pre-BCR) leads to activation of the adaptor molecule Slp65 (also termed Bash or Blnk) and Btk. Spontaneous pre-B cell leukemia development in Slp65-deficient mice demonstrate that Slp65 acts as a tumor suppressor. Slp65 and Btk have a synergistic role in the developmental progression of large cycling into small resting pre-B cells. Btk/Slp65 double mutant mice have a dramatically increased pre-B cell tumor incidence (approximately 75%, 16 wk of age), as compared with Slp65 single deficient mice (<10%). Therefore, Btk cooperates with Slp65 as a tumor suppressor in pre-B cells. Moreover, transgenic expression of a constitutive active form of Btk, the E41K-Y223F mutant, prevented tumor formation in Btk/Slp65 double mutant mice, indicating that constitutive active Btk can substitute for Slp65 as a tumor suppressor. Using a kinase-inactive K430R-Btk mutant, it was shown that Btk exerts its tumor suppressor function in pre-B cells as an adaptor protein, independent of its catalytic activity. Furthermore, loss of Btk and Tec increases the tumor frequency in Eµ-myc transgenic mice, expressing the c-myc oncogenic transcription factor that promotes both proliferation and differentiation.
Entity name
X-linked agammaglobulinemia (XLA).
Note
In 1993 BTK was identified as the gene defective in the human immunodeficiency disease X-linked agammaglobulinemia (XLA). The XLA disease, which was first described by Dr. O.C. Bruton in 1952, is characterized by protracted and recurrent bacterial infections.
Clinical manifestations of XLA
XLA Patients have less than 1% of the normal number of peripheral B cells. Serum levels of all Ig classes are very low due to the lack of plasma cells in the secondary lymphoid organs. In XLA patients, B cell development is almost completely arrested at the pre-B cell stage: the pre-B cell fraction mainly consists of small cells, suggesting that Btk is necessary for their proliferative expansion. Heterozygous female XLA carriers do not have clinical or immunological symptoms, but manifest a unilateral X chromosome inactivation in the peripheral blood B lymphocyte population, because of a selective disadvantage of cells that have the defective Btk gene on the active X chromosome. In contrast to XLA, Btk-deficiency in the mouse, termed X-linked immunodeficiency (xid), is associated with a very mild early B cell developmental block, but with impaired maturation and poor survival of peripheral B cells. XLA is a heterogeneous disease, even within single families and no correlation has been observed between the position of the mutation and phenotypic variables, such as age at time of diagnosis or severity of the clinical or immunological symptoms. Therefore, this heterogeneity might be related to other genetic or environmental factors.
Mutations in BTK gene that cause XLA
The BTK mutations that have been identified in XLA patients compromise BTK function either through gross structural changes (such as deletions or altered protein folding) or through specific loss of functionally relevant residues. Strikingly, none of the found unique missense mutations found in XLA patients is located in the SH3 domain of BTK, which harbors the Y223 tyrosine residue. An international registry for XLA (http://bioinf.uta.fi/BTKbase/) shows that mutations in all domains of the BTK gene cause the disease.
Approximately 80-90% of the patients that have agammaglobulinemia patients have a deficiency of the BTK protein. The other about 15% of the agammaglobulinemia cases are caused by defects in autosomal genes such as the constant region of immunoglobulin (Ig) heavy chain, λ5, (IGLL), Igα (CD79a), Igβ (CD79b), or SLP65 (BLNK) resemble the clinical manifestation of XLA.

Bibliography

Pubmed IDLast YearTitleAuthors
161413232005Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells.Feldhahn N et al
128549032003Defective expression of Bruton's tyrosine kinase in acute lymphoblastic leukemia.Goodman PA et al
179983972007Myc stimulates B lymphocyte differentiation and amplifies calcium signaling.Habib T et al
176840992007The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib.Hantschel O et al
163009602006Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells.Hendriks RW et al
157715772005B cell signaling and tumorigenesis.Jumaa H et al
128354822003Bruton's tyrosine kinase cooperates with the B cell linker protein SLP-65 as a tumor suppressor in Pre-B cells.Kersseboom R et al
75529941995Defective B cell development and function in Btk-deficient mice.Khan WN et al
75384391995Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain.Li T et al
100926451999Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide].Mahajan S et al
153314452005Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity.Middendorp S et al
108871252000Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway.Nomura K et al
86307361996Regulation of Btk function by a major autophosphorylation site within the SH3 domain.Park H et al
84252211993Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.Tsukada S et al
173674102007Bruton's tyrosine kinase prevents activation of the anti-apoptotic transcription factor STAT3 and promotes apoptosis in neoplastic B-cells and B-cell precursors exposed to oxidative stress.Uckun F et al
86880941996BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells.Uckun FM et al
169697612006BTKbase: the mutation database for X-linked agammaglobulinemia.Väliaho J et al
83809051993The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.Vetrie D et al

Other Information

Locus ID:

NCBI: 695
MIM: 300300
HGNC: 1133
Ensembl: ENSG00000010671

Variants:

dbSNP: 695
ClinVar: 695
TCGA: ENSG00000010671
COSMIC: BTK

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000010671ENST00000308731Q06187
ENSG00000010671ENST00000372880Q5JY90
ENSG00000010671ENST00000618050U3NG26
ENSG00000010671ENST00000621635Q06187

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
B cell receptor signaling pathwayKEGGko04662
Fc epsilon RI signaling pathwayKEGGko04664
Primary immunodeficiencyKEGGko05340
B cell receptor signaling pathwayKEGGhsa04662
Fc epsilon RI signaling pathwayKEGGhsa04664
Primary immunodeficiencyKEGGhsa05340
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
Platelet activationKEGGhsa04611
DiseaseREACTOMER-HSA-1643685
Diseases of Immune SystemREACTOMER-HSA-5260271
Diseases associated with the TLR signaling cascadeREACTOMER-HSA-5602358
IRAK4 deficiency (TLR2/4)REACTOMER-HSA-5603041
MyD88 deficiency (TLR2/4)REACTOMER-HSA-5602498
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Antigen activates B Cell Receptor (BCR) leading to generation of second messengersREACTOMER-HSA-983695
Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
Antigen processing-Cross presentationREACTOMER-HSA-1236975
ER-Phagosome pathwayREACTOMER-HSA-1236974
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Regulation of actin dynamics for phagocytic cup formationREACTOMER-HSA-2029482
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated Ca+2 mobilizationREACTOMER-HSA-2871809
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases Activate WASPs and WAVEsREACTOMER-HSA-5663213

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA166121346ibrutinibChemicalLiterature, MultilinkAnnotationassociated24697238, 24869598

References

Pubmed IDYearTitleCitations
248695982014Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.277
214224732011Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.250
267156452016Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.122
246582732014Targeting Bruton's tyrosine kinase in B cell malignancies.92
127243222003Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4.87
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
260596592015Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury.73
243117222014Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL).69
164393612006MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transduction.65
226898602012Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma.62

Citation

Rudi W Hendriks ; Pieter Fokko van Loo

BTK (Bruton agammaglobulinemia tyrosine kinase)

Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

Online version: http://atlasgeneticsoncology.org/gene/851/btk