Molecule Information

General Information of the Molecule (ID: Mol00262)

• Name: Tyrosine-protein kinase BTK (BTK) ,Homo sapiens
• Synonyms: Agammaglobulinemia tyrosine kinase; ATK; B-cell progenitor kinase; BPK; Bruton tyrosine kinase; AGMX1; ATK; BPK
• Molecule Type: Protein
• Gene Name: BTK
• Gene ID: 695
• Location: chrX:101349338-101390796[-]
• Sequence:
  MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEK
  ITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEEL
  RKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSS
  HRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDE
  YFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGK
  EGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELIN
  YHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGK
  WRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANG
  CLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDF
  GLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER
  FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES
• 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.
• Uniprot ID: BTK_HUMAN
• Ensembl ID: ENSG00000010671
• HGNC ID: HGNC:1133

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic lymphocytic leukemia [1]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481R
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Disease Class: Chronic lymphocytic leukemia [1]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Sanger sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay; Bone marrow biopsy assay; Lymph node biopsy assay; Physical and laboratory examinations assay; Computed tomography imaging assay
• Mechanism Description: All patients except one had an early on-treatment sample available that tested negative for BTk and PLCG2 mutations, indicating expansion of subclones carrying drug-resistant mutations during treatment. Most cases of ibrutinib-resistant CLL were due to mutations in BTk and,or PLCG2 and often composed of multiple independent subclones.

Disease Class: Mantle cell lymphoma [2]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mantle cell lymphoma isolates; Peripheral blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-transcriptome sequencing assay
• Mechanism Description: This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance.

Disease Class: Mantle cell lymphoma [2]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mantle cell lymphoma isolates; Peripheral blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-exome sequencing assay; Whole-transcriptome sequencing assay
• Mechanism Description: This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance.

Disease Class: Mantle cell lymphoma [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PIK3/AKT signaling pathway; Activation; hsa04211
• Mechanism Description: Efforts have been made to understand the functional consequences of the BTK mutation. On a structural level, the C481S mutation disrupts covalent binding, allowing for reversible, instead of strong irreversible, binding of BTK by ibrutinib. The critical biochemical role of covalent-bond formation was revealed when fluorescently tagged-ibrutinib labelled the wild-type (WT) BTK, but not the BTKC481S mutant.

Disease Class: Chronic lymphocytic leukemia [3]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Missense mutation; p.C481S
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Efforts have been made to understand the functional consequences of the BTK mutation. On a structural level, the C481S mutation disrupts covalent binding, allowing for reversible, instead of strong irreversible, binding of BTK by ibrutinib. The critical biochemical role of covalent-bond formation was revealed when fluorescently tagged-ibrutinib labelled the wild-type (WT) BTK, but not the BTKC481S mutant.

References

• Ref 1: Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017 Mar 16;129(11):1469-1479. doi: 10.1182/blood-2016-06-719294. Epub 2017 Jan 3.
• Ref 2: Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects .Br J Haematol. 2018 May;181(3):306-319. doi: 10.1111/bjh.15108. Epub 2018 Jan 23. 10.1111/bjh.15108
• Ref 3: Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma .Br J Haematol. 2015 Aug;170(4):445-56. doi: 10.1111/bjh.13427. Epub 2015 Apr 9. 10.1111/bjh.13427