Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA)

Vihinen, Mauno; Mattsson, PT; Smith, C. I. Edvard

doi:10.2741/vihinen

Cited by 43 publications

(48 citation statements)

References 133 publications

(128 reference statements)

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“…The human disease X-linked agammaglobulinemia results from mutations in BTK that cause profound defects in B cell development and mature B cell function (5). BTK is also a close homolog of the Tec and Itk kinases that play important signaling roles in other hematopoietic and some non-hematopoietic cell types (10,11).…”

Section: Discussionmentioning

confidence: 99%

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Activation Mechanism and Steady State Kinetics of Bruton's Tyrosine Kinase

Dinh¹,

Grünberger

Ho³

et al. 2007

Journal of Biological Chemistry

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Bruton's tyrosine kinase (BTK) is a member of the Tec nonreceptor tyrosine kinase family that is involved in regulating B cell proliferation. To better understand the enzymatic mechanism of the Tec family of kinases, the kinetics of BTK substrate phosphorylation were characterized using a radioactive enzyme assay. We first examined whether autophosphorylation regulates BTK activity. Western blotting with a phosphospecific antibody revealed that BTK rapidly autophosphorylates at Tyr 551 within its activation loop in vitro. Examination of a Y551F BTK mutant indicated that phosphorylation of Tyr 551 causes a 10-fold increase in BTK activity. We then proceeded to characterize the steady state kinetic mechanism of BTK. Varying the concentrations of ATP and S1 peptide (biotin-Aca-AAAEEIY-GEI-NH 2 ) revealed that BTK employs a ternary complex mechanism with K mATP ‫؍‬ 84 ؎ 20 M and K mS1 ‫؍‬ 37 ؎ 8 M. Inhibition studies were also performed to examine the order of substrate binding. The inhibitors ADP and staurosporine were both found to be competitive with ATP and non-competitive with S1, indicating binding of ATP and S1 to BTK is either random or ordered with ATP binding first. Negative cooperativity was also found between the S1 and ATP binding sites. Unlike ATP site inhibitors, substrate analog inhibitors did not inhibit BTK at concentrations less than 1 mM, suggesting that BTK may employ a "substrate clamping" type of kinetic mechanism whereby the substrate K d is weaker than K m . This investigation of BTK provides the first detailed kinetic characterization of a Tec family kinase. Bruton's tyrosine kinase (BTK)2 is a non-receptor tyrosine kinase that plays an essential role in B cells and other hematopoietic cell types (1-4). The importance of BTK is evident from the fact that mutations in BTK cause X-linked agammaglobulinemia, a human disease that causes defects in both B cell maturation and mature B cell function (5, 6). A BTK point mutation in mice results in a similar, albeit milder, B cell deficiency known as X-linked immunodeficiency (7). The indispensable requirement of BTK for B cell function in humans makes BTK a promising target for treatment of inflammatory diseases that involve inappropriate B cell activation.The BTK-mediated signaling events that link B cell receptor ligation to downstream signaling have been well characterized (8, 9). Upon ligation of the B cell receptor, Src family kinases associated with the receptor, such as Lyn, are the first enzymes activated. This activation results in phosphorylation of tyrosine residues that become docking sites for other kinases including phosphatidylinositol 3-kinase. Once recruited, phosphatidylinositol 3-kinase phosphorylates phosphatidylinositol 4,5-bisphosphate to form phosphatidylinositol 3,4,5-bisphosphate. Formation of phosphatidylinositol 3,4,5-bisphosphate then recruits BTK to the plasma membrane via interaction with its pleckstrin homology domain. Upon recruitment to the membrane, BTK is activated via phosphorylation. BTK proceeds to phosphorylat...

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Section: Discussionmentioning

confidence: 99%

“…The importance of BTK is evident from the fact that mutations in BTK cause X-linked agammaglobulinemia, a human disease that causes defects in both B cell maturation and mature B cell function (5,6). A BTK point mutation in mice results in a similar, albeit milder, B cell deficiency known as X-linked immunodeficiency (7).…”

Section: Bruton's Tyrosine Kinase (Btk)mentioning

confidence: 99%

Activation Mechanism and Steady State Kinetics of Bruton's Tyrosine Kinase

Dinh¹,

Grünberger

Ho³

et al. 2007

Journal of Biological Chemistry

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“…A large body of work indicates that these kinases are critical for antigen receptor signaling in B and T cells. Humans or mice carrying mutations in BTK develop aggamaglobulinemia (humans) or X-linked immunodeficiency (mice) due to defects in B cell maturation, as well as B cell activation [2]. Similarly, mice lacking ITK exhibit defects in T cell maturation, although not as severe as BTK, perhaps due to compensation from the other Tec kinase expressed in T cells, Rlk/ Txk, since ITK/Rlk double knockouts exhibit more severe phenotypes [3,4].…”

Section: Introductionmentioning

confidence: 99%

A kinase independent function for Tec kinase ITK in regulating antigen receptor induced serum response factor activation

Hao¹,

Qi²,

Hu³

et al. 2006

FEBS Letters

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The Tec family kinases are critical downstream regulators of antigen receptor signals in lymphocytes. As kinases, they act on critical substrates to regulate signals such as calcium increase leading to activation of transcription factors such as NFAT, NFjB and SRF. We now show here that ITK, a member of the Tec family of tyrosine kinases, has a kinase independent function. Mutants of ITK that lack kinase activity or a kinase domain can rescue cells lacking Tec family kinases for antigen receptor induced SRF activation, but not for NFAT, AP-1 or NFjB activation. Furthermore, expression of these mutants in WT cells enhanced SRF activation. This kinase independent function required the SH2 domain since a mutant lacking both the kinase and SH2 domains was much less effective at rescuing SRF activation. This kinase-deleted mutant could partially rescue ERK activation, and interact with multiple tyrosine phosphorylated proteins during antigen receptor signaling, suggesting that ITK uses a scaffolding function that regulates signals leading to specific regulation of SRF activation.

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“…Btk is preferentially expressed in B cells and is necessary for B-cell development (Kerner et al, 1995;Khan et al, 1995). Mutations in the Btk gene result in human X-linked agammaglobulinemia and murine X-linked immunodeficiency (Tsukada et al, 1993;Satterthwaite et al, 1998;Vihinen et al, 2000). Likewise, Itk is predominately expressed in T cells and is crucial in T-cell development and T-cell receptorinitiated signaling cascade (Bunnell et al, 2000;August et al, 2002;Miller and Berg, 2002).…”

Section: Introductionmentioning

confidence: 99%