BioPAX pathway converted from "PIP3:BTK:G beta-gamma complex dissociates to Active BTK, PIP3 and G beta-gamma complex" in the Reactome database.PIP3:BTK:G beta-gamma complex dissociates to Active BTK, PIP3 and G beta-gamma complexPIP3:BTK:G beta-gamma complex dissociates to Active BTK, PIP3 and G beta-gamma complexG-Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins (G-proteins) that have alpha, beta and gamma subunits. Upon activation, the alpha subunit of G-proteins dissociates from beta-gamma and the both are then free to regulate downstream effectors. G-protein beta-gamma complex, along with phosphatidylinositol 3,4,5-trisphosphate (PIP3), recruits the non-receptor Tyrosine-protein kinase BTK to the cell membrane. Here, the G-protein beta-gamma complex activates BTK. Once active, BTK dissociates from PIP3 and G-protein beta-gamma complex and is released to the cytoplasm to phosphorylate downstream substrates. Physiologically, BTK plays a key role in B lymphocyte development, differentiation and signalling.Authored: Varusai, Thawfeek, 2017-07-27Reviewed: Huang, Xin-Yun, 2018-09-13Edited: Varusai, Thawfeek, 2017-07-27Reactome DB_ID: 89642671plasma membraneGO0005886PIP3:Active BTK:G-protein beta-gamma complex [plasma membrane]PIP3:Active BTK:G-protein beta-gamma complexReactome DB_ID: 89643231cytosolGO0005829UniProt:Q06187 BTKBTKAGMX1BTKATKBPKFUNCTION 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.ACTIVITY REGULATION Activated by phosphorylation. In primary B lymphocytes, is almost always non-phosphorylated and is thus catalytically inactive. Stimulation of TLR8 and TLR9 causes BTK activation. As a negative feedback mechanism to fine-tune BCR signaling, activated PRKCB down-modulates BTK function via direct phosphorylation of BTK at Ser-180, resulting in translocation of BTK back to the cytoplasmic fraction. PIN1, SH3BP5, and IBTK were also identified as BTK activity inhibitors. Interaction with CAV1 leads to dramatic down-regulation of the kinase activity of BTK. LFM-13A is a specific inhibitor of BTK. Dasatinib, a cancer drug acting as a tyrosine kinase inhibitor, also blocks BTK activity.SUBUNIT Binds GTF2I through the PH domain. Interacts with SH3BP5 via the SH3 domain. Interacts with IBTK via its PH domain. Interacts with ARID3A, CAV1, FASLG, PIN1, TLR8 and TLR9.TISSUE SPECIFICITY Predominantly expressed in B-lymphocytes.DOMAIN The PH domain mediates the binding to inositol polyphosphate and phosphoinositides, leading to its targeting to the plasma membrane. It is extended in the BTK kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain.PTM Following B-cell receptor (BCR) engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-551 by LYN and SYK. Phosphorylation at Tyr-551 is followed by autophosphorylation of Tyr-223 which may create a docking site for a SH2 containing protein. Phosphorylation at Ser-180 by PRKCB, leads in translocation of BTK back to the cytoplasmic fraction. Phosphorylation at Ser-21 and Ser-115 creates a binding site for PIN1 at these Ser-Pro motifs, and promotes it's recruitment.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtQ06187Chain Coordinates2EQUAL659EQUALReactome DB_ID: 17983811-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618]1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphatePIP3ChEBI16618Reactome DB_ID: 1674341G-protein beta-gamma complex [plasma membrane]G-protein beta-gamma complexConverted from EntitySet in ReactomeReactome DB_ID: 68144131G-protein beta subunit [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGNB1 [cytosol]UniProtP62873Converted from EntitySet in ReactomeReactome DB_ID: 1674421G-protein gamma subunit [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGNG2 [plasma membrane]UniProtP59768Reactome Database ID Release 71167434Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=167434ReactomeR-HSA-1674343Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-167434.3Reactome Database ID Release 718964267Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8964267ReactomeR-HSA-89642671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8964267.1Reactome DB_ID: 896432312EQUAL659EQUALReactome DB_ID: 1798381Reactome DB_ID: 1674341Reactome Database ID Release 718964317Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8964317ReactomeR-HSA-89643171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8964317.111698416Pubmed2002G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton's agammaglobulinemia tyrosine kinaseLowry, William EHuang, Xin-YunJ. Biol. Chem. 277:1488-927567982Pubmed1995Activation of Tsk and Btk tyrosine kinases by G protein beta gamma subunitsLanghans-Rajasekaran, S AWan, YHuang, X YProc. Natl. Acad. Sci. U.S.A. 92:8601-5