InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: BTK

Summary

InnateDB Protein

IDBP-79655.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

BTK

Protein Name

Bruton agammaglobulinemia tyrosine kinase

Synonyms

AGMX1; AT; ATK; BPK; IMD1; PSCTK1; XLA;

Species

Homo sapiens

Ensembl Protein

ENSP00000308176

InnateDB Gene

IDBG-79651 (BTK)

Protein Structure

UniProt Annotation

Function

Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. {ECO:0000269PubMed:11606584, ECO:0000269PubMed:16415872, ECO:0000269PubMed:16517732, ECO:0000269PubMed:16738337, ECO:0000269PubMed:17932028, ECO:0000269PubMed:9012831}.

Subcellular Localization

Cytoplasm. Cell membrane; Peripheral membrane protein. Nucleus. Note=In steady state, BTK is predominantly cytosolic. Following B-cell receptor (BCR) engagement by antigen, translocates to the plasma membrane through its PH domain. Plasma membrane localization is a critical step in the activation of BTK. A fraction of BTK also shuttles between the nucleus and the cytoplasm, and nuclear export is mediated by the nuclear export receptor CRM1.

Disease Associations

X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin. {ECO:0000269PubMed:10220140, ECO:0000269PubMed:10612838, ECO:0000269PubMed:10678660, ECO:0000269PubMed:7627183, ECO:0000269PubMed:7633420, ECO:0000269PubMed:7633429, ECO:0000269PubMed:7711734, ECO:0000269PubMed:7809124, ECO:0000269PubMed:7849006, ECO:0000269PubMed:7849697, ECO:0000269PubMed:7849721, ECO:0000269PubMed:7880320, ECO:0000269PubMed:7897635, ECO:0000269PubMed:8013627, ECO:0000269PubMed:8162018, ECO:0000269PubMed:8162056, ECO:0000269PubMed:8634718, ECO:0000269PubMed:8695804, ECO:0000269PubMed:8723128, ECO:0000269PubMed:8834236, ECO:0000269PubMed:9260159, ECO:0000269PubMed:9280283, ECO:0000269PubMed:9445504, ECO:0000269PubMed:9545398}. Note=The disease is caused by mutations affecting the gene represented in this entry.X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD). Note=The disease may be caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Predominantly expressed in B-lymphocytes.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 106 experimentally validated interaction(s) in this database.
They are also associated with 37 interaction(s) predicted by orthology.

Experimentally validated
Total	106 [view]
Protein-Protein	104 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	37 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004715	non-membrane spanning protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0005547	phosphatidylinositol-3,4,5-trisphosphate binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0042802	identical protein binding
GO:0046872	metal ion binding

Biological Process

GO:0002224	toll-like receptor signaling pathway
GO:0002250	adaptive immune response
GO:0002721	regulation of B cell cytokine production
GO:0002755	MyD88-dependent toll-like receptor signaling pathway
GO:0002902	regulation of B cell apoptotic process
GO:0006351	transcription, DNA-templated
GO:0006468	protein phosphorylation
GO:0007498	mesoderm development
GO:0019722	calcium-mediated signaling
GO:0034134	toll-like receptor 2 signaling pathway
GO:0034142	toll-like receptor 4 signaling pathway
GO:0035556	intracellular signal transduction
GO:0038095	Fc-epsilon receptor signaling pathway
GO:0038123	toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124	toll-like receptor TLR6:TLR2 signaling pathway
GO:0042113	B cell activation
GO:0045087	innate immune response (InnateDB)
GO:0045579	positive regulation of B cell differentiation
GO:0050853	B cell receptor signaling pathway
GO:0051092	positive regulation of NF-kappaB transcription factor activity
GO:0097190	apoptotic signaling pathway

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0043231	intracellular membrane-bounded organelle
GO:0045121	membrane raft

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR000980 SH2 domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR001452 SH3 domain
IPR001562 Zinc finger, Btk motif
IPR001849 Pleckstrin homology domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR011511 Variant SH3 domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM