Mutagenesis analysis of IP4 binding sites in the PH domain of Bruton's tyrosine kinase

2000 ◽  
Vol 28 (5) ◽  
pp. A428-A428
Author(s):  
M. Fink ◽  
P. Vergès ◽  
C. Andrianjara ◽  
J. Allen
Keyword(s):  
Tyrosine Kinase ◽  
Binding Sites ◽  
Bruton’S Tyrosine Kinase ◽  
Ph Domain ◽  
Bruton's Tyrosine Kinase

scholarly journals The PH Domain and the Polybasic c Domain of Cytohesin-1 Cooperate specifically in Plasma Membrane Association and Cellular Function

1998 ◽  
Vol 9 (8) ◽  
pp. 1981-1994 ◽  
Author(s):  
Wolfgang Nagel ◽  
Pierre Schilcher ◽  
Lutz Zeitlmann ◽  
Waldemar Kolanus
Keyword(s):  
Plasma Membrane ◽  
Cell Adhesion ◽  
Tyrosine Kinase ◽  
Biological Function ◽  
Common Mechanism ◽  
Membrane Association ◽  
Bruton’S Tyrosine Kinase ◽  
Ph Domain ◽  
Bruton's Tyrosine Kinase ◽  
Ph Domains

Recruitment of intracellular proteins to the plasma membrane is a commonly found requirement for the initiation of signal transduction events. The recently discovered pleckstrin homology (PH) domain, a structurally conserved element found in ∼100 signaling proteins, has been implicated in this function, because some PH domains have been described to be involved in plasma membrane association. Furthermore, several PH domains bind to the phosphoinositides phosphatidylinositol-(4,5)-bisphosphate and phosphatidylinositol-(3,4,5)-trisphosphate in vitro, however, mostly with low affinity. It is unclear how such weak interactions can be responsible for observed membrane binding in vivo as well as the resulting biological phenomena. Here, we investigate the structural and functional requirements for membrane association of cytohesin-1, a recently discovered regulatory protein of T cell adhesion. We demonstrate that both the PH domain and the adjacent carboxyl-terminal polybasic sequence of cytohesin-1 (c domain) are necessary for plasma membrane association and biological function, namely interference with Jurkat cell adhesion to intercellular adhesion molecule 1. Biosensor measurements revealed that phosphatidylinositol-(3,4,5)-trisphosphate binds to the PH domain and c domain together with high affinity (100 nM), whereas the isolated PH domain has a substantially lower affinity (2–3 μM). The cooperativity of both elements appears specific, because a chimeric protein, consisting of the c domain of cytohesin-1 and the PH domain of the β-adrenergic receptor kinase does not associate with membranes, nor does it inhibit adhesion. Moreover, replacement of the c domain of cytohesin-1 with a palmitoylation–isoprenylation motif partially restored the biological function, but the specific targeting to the plasma membrane was not retained. Thus we conclude that two elements of cytohesin-1, the PH domain and the c domain, are required and sufficient for membrane association. This appears to be a common mechanism for plasma membrane targeting of PH domains, because we observed a similar functional cooperativity of the PH domain of Bruton’s tyrosine kinase with the adjacent Bruton’s tyrosine kinase motif, a novel zinc-containing fold.

Phosphoinositide3-Kinase Independent Regulation of Bruton’s Tyrosine Kinase in Platelet Immunoreceptor Signaling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3536-3536
Author(s):  
Naohide Watanabe ◽  
Hideaki Nakajima ◽  
Atsushi Oda ◽  
Yasuo Ikeda ◽  
Makoto Handa
Keyword(s):  
Tyrosine Kinase ◽  
Gene Knockout ◽  
Antigen Receptor ◽  
Cellular Responses ◽  
Bruton’S Tyrosine Kinase ◽  
Dependent Manner ◽  
Ph Domain ◽  
Bruton's Tyrosine Kinase ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Abstract Phosphoinositide 3-kinase (PI3K)-dependent activation of Bruton’s tyrosine kinase (Btk) is an indispensable step of B cell antigen receptor (BCR)-mediated signaling leading to cell development and function. Btk is a cytosolic tyrosine kinase and its recruitment to the plasma membrane is a necessary step for its function. In the BCR pathway, class 1A PI3K is though to play a major role in Btk recruitment by generating the D3 phosphoinositide as a docking site for the pleckstrin homology (PH) domain of this effecter kinase. This widely accepted hypothesis has been tested in platelets from gene knockout or mutant mice, since the cells utilize sets of transducers in collagen-induced GP VI signaling similar to those involved in immunoreceptor tyrosine-based activation motif-mediated signaling cascades activated by BCR and T cell antigen receptor (TCR) ligation. GP VI stimulation by collagen or collagen related peptide induces cellular responses including aggregation, granular secretion and adhesion, and Btk/phospholipase C (PLC) γ2 activation. As compared with control mice, these cellular responses and PLCγ2 tyrosine phosphorylation of either Btk or PI3K p85α−/− platelets were readily impaired, but the defect was greater in Btk−/− than p85α−/− platelets. Most strikingly, platelets from double-deficiency mice showed a most severely compromised phenotype implying the existence of a PI3K-independent pathway for Btk activation. Moreover, unlike B cells, as compared with Btk−/− platelets, only subtle functional defect was observed in X-linked immunodeficiency (Xid) platelets in which PI3K-dependent Btk activation is selectively lacking due to a naturally occurring point mutation of the gene encoding the PH domain of the kinase. In the TCR pathway, an adaptor complex formed by LAT, Gads and SLP-76 proteins that is membrane-bound via LAT palmitoylation readily recruits Itk, which is a counterpart Btk/Tec family kinase specific for TCR. Indeed, Btk was found to be associated with LAT/Gads/SLP-76 complex in platelets in a GP VI-stimulation dependent manner, and this phenomenon was unaffected by either PI3K defect or PI3K inhibitor. These results indicate that in platelet immunoreceptor signaling, Btk function is under control, at least in part, by a mechanism independent of PI3K engagement.

scholarly journals Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate

Structure ◽  
1999 ◽  
Vol 7 (4) ◽  
pp. 449-460 ◽  
Author(s):  
Elena Baraldi ◽  
Kristina Djinovic Carugo ◽  
Marko Hyvönen ◽  
Paola Lo Surdo ◽  
Andrew M Riley ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Bruton’S Tyrosine Kinase ◽  
Ph Domain ◽  
Bruton's Tyrosine Kinase

scholarly journals Activation of bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain

Immunity ◽  
1995 ◽  
Vol 2 (5) ◽  
pp. 451-460 ◽  
Author(s):  
Tianjian Li ◽  
Satoshi Tsukada ◽  
Anne Satterthwaite ◽  
Marie H. Havlik ◽  
Hyunsun Park ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Point Mutation ◽  
Bruton’S Tyrosine Kinase ◽  
Ph Domain ◽  
Pleckstrin Homology ◽  
Bruton's Tyrosine Kinase

Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain

2009 ◽  
Vol 228 (1) ◽  
pp. 58-73 ◽  
Author(s):  
Abdalla J. Mohamed ◽  
Liang Yu ◽  
Carl-Magnus Bäckesjö ◽  
Leonardo Vargas ◽  
Rani Faryal ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Bruton’S Tyrosine Kinase ◽  
Ph Domain ◽  
Bruton's Tyrosine Kinase

Crystal structure of the Bruton’s tyrosine kinase PH domain with phosphatidylinositol

2008 ◽  
Vol 377 (1) ◽  
pp. 23-28 ◽  
Author(s):  
Kazutaka Murayama ◽  
Miyuki Kato-Murayama ◽  
Chiemi Mishima ◽  
Ryogo Akasaka ◽  
Mikako Shirouzu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Tyrosine Kinase ◽  
Bruton’S Tyrosine Kinase ◽  
Ph Domain ◽  
Bruton's Tyrosine Kinase
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