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Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK

Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultim...

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Autores principales: Kueffer, Lauren E., Joseph, Raji E., Andreotti, Amy H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260988/
https://www.ncbi.nlm.nih.gov/pubmed/34249912
http://dx.doi.org/10.3389/fcell.2021.655489
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author Kueffer, Lauren E.
Joseph, Raji E.
Andreotti, Amy H.
author_facet Kueffer, Lauren E.
Joseph, Raji E.
Andreotti, Amy H.
author_sort Kueffer, Lauren E.
collection PubMed
description Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies.
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spelling pubmed-82609882021-07-08 Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK Kueffer, Lauren E. Joseph, Raji E. Andreotti, Amy H. Front Cell Dev Biol Cell and Developmental Biology Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies. Frontiers Media S.A. 2021-06-23 /pmc/articles/PMC8260988/ /pubmed/34249912 http://dx.doi.org/10.3389/fcell.2021.655489 Text en Copyright © 2021 Kueffer, Joseph and Andreotti. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Kueffer, Lauren E.
Joseph, Raji E.
Andreotti, Amy H.
Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK
title Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK
title_full Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK
title_fullStr Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK
title_full_unstemmed Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK
title_short Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK
title_sort reining in btk: interdomain interactions and their importance in the regulatory control of btk
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260988/
https://www.ncbi.nlm.nih.gov/pubmed/34249912
http://dx.doi.org/10.3389/fcell.2021.655489
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