A fraction of Bruton's tyrosine kinase (Btk) co-localizes with actin fibers upon stimulation of mast cells via the high affinity IgE receptor (FcεRI). In this study, a molecular basis of the Btk co-localization with actin fibers is presented. Btk and other Tec family tyrosine kinases have a pleckstrin homology (PH) domain at their N termini. The PH domain is a short peptide module frequently found in signal-transducing proteins and cytoskeletal proteins. Filamentous actin (F-actin) is shown to be a novel ligand for a subset of PH domains, including that of Btk. The actin-binding site was mapped to a 10-residue region of the N-terminal region of Btk. Basic residues in this short stretch are demonstrated to be involved in actin binding. Isolated PH domains induced actin filament bundle formation. Consistent with these observations, Btk binds F-actinin vitro and in vivo. Wild-type Btk protein is in part translocated to the cytoskeleton upon FcεRI cross-linking, whereas Btk containing a mutated PH domain is not. Phosphatidylinositol 3,4,5-trisphosphate-mediated membrane translocation of Btk was enhanced in cytochalasind-pretreated, FcεRI-stimulated mast cells. These data indicate that PH domain-mediated F-actin binding plays a role in Btk co-localization with actin filaments. A fraction of Bruton's tyrosine kinase (Btk) co-localizes with actin fibers upon stimulation of mast cells via the high affinity IgE receptor (FcεRI). In this study, a molecular basis of the Btk co-localization with actin fibers is presented. Btk and other Tec family tyrosine kinases have a pleckstrin homology (PH) domain at their N termini. The PH domain is a short peptide module frequently found in signal-transducing proteins and cytoskeletal proteins. Filamentous actin (F-actin) is shown to be a novel ligand for a subset of PH domains, including that of Btk. The actin-binding site was mapped to a 10-residue region of the N-terminal region of Btk. Basic residues in this short stretch are demonstrated to be involved in actin binding. Isolated PH domains induced actin filament bundle formation. Consistent with these observations, Btk binds F-actinin vitro and in vivo. Wild-type Btk protein is in part translocated to the cytoskeleton upon FcεRI cross-linking, whereas Btk containing a mutated PH domain is not. Phosphatidylinositol 3,4,5-trisphosphate-mediated membrane translocation of Btk was enhanced in cytochalasind-pretreated, FcεRI-stimulated mast cells. These data indicate that PH domain-mediated F-actin binding plays a role in Btk co-localization with actin filaments. Bruton's tyrosine kinase bone marrow-derived mouse mast cells dinitrophenyl filamentous actin the high affinity IgE receptor globular actin glutathioneS-transferase oxysterol-binding protein pleckstrin homology phosphatidylinositol 4,5-bisphosphate phosphatidylinositol 3,4,5-trisphosphate protein kinase C phospholipase C protein-tyrosine kinase Src homology Tec homology monoclonal antibody polyacrylamide gel electrophoresis polymerase chain reaction myristoylated alanine-rich C kinase substrate Btk,1 a cytoplasmic protein-tyrosine kinase (PTK), is implicated in signal transduction initiated by numerous immune cell receptors including FcεRI and B cell antigen receptor (reviewed in Refs. 1Satterthwaite A.B. Li Z. Witte O.N. Semin. Immunol. 1998; 10: 309-316Crossref PubMed Scopus (158) Google Scholar and 2Kawakami Y. Kitaura J. Hata D. Yao L. Kawakami T. J. Leukocyte Biol. 1999; 65: 286-290Crossref PubMed Scopus (75) Google Scholar). Similar to other signaling proteins (3Cohen G.B. Ren R. Baltimore D. Cell. 1995; 80: 237-248Abstract Full Text PDF PubMed Scopus (925) Google Scholar, 4Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2229) Google Scholar), Btk is composed of several functional domains as follows: pleckstrin homology (PH), Tec homology (TH), Src homology (SH) 3, SH2, and SH1 (=kinase) domains in this order from N to C termini. Unlike Src family PTKs, Btk lacks the N-terminal myristoylation site and the C-terminal negative regulatory tyrosine residue (corresponding to Tyr-527 in pp60c-src). Upon B cell receptor stimulation, Btk is recruited to the plasma membrane through the interaction between the PH domain and phosphatidylinositol 3,4,5-trisphosphate (PIP3) (5Li Z. Wahl M.I. Eguinoa A. Stephens L.R. Hawkins P.T. Witte O.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13820-13825Crossref PubMed Scopus (187) Google Scholar, 6Scharenberg A.M. El-Hillal O. Fruman D.A. Beitz L.O. Li Z. Lin S. Gout I. Cantley L.C. Rawlings D.J. Kinet J.-P. EMBO J. 1998; 17: 1961-1972Crossref PubMed Scopus (386) Google Scholar, 7Fluckiger A.-C. Li Z. Kato R.M. Wahl M.I. Ochs H.D. Longnecker R. Kinet J.-P. Witte O.N. Scharenberg A.M. Rawlings D.J. EMBO J. 1998; 17: 1973-1985Crossref PubMed Scopus (358) Google Scholar). Then it is activated by phosphorylation at the activation loop (Tyr-551) by Lyn or Syk (8Rawlings D.J. Scharenberg A.M. Park H. Wahl M.I. Lin S. Kato R.M. Fluckiger A.-C. Witte O.N. Kinet J.-P. Science. 1996; 271: 822-825Crossref PubMed Scopus (379) Google Scholar, 9Kurosaki T. Kurosaki M. J. Biol. Chem. 1997; 272: 15595-15598Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). The phosphorylated Btk exhibits increased kinase activity and autophosphorylates at Tyr-231 (10Park H. Wahl M.I. Afar D.E.H. Turck C.W. Rawlings D.J. Tam C. Scharenberg A.M. Kinet J.-P. Witte O.N. Immunity. 1996; 4: 515-525Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). Since the proline-rich sequence in the TH domain has the capacity to interact with the SH3 domains of Src family PTKs (11Cheng G. Ye Z.-S. Baltimore D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8152-8155Crossref PubMed Scopus (166) Google Scholar), this interaction may be involved in Lyn phosphorylation of Btk. Btk regulates tyrosine phosphorylation of phospholipase C (PLC)-γ2 (and probably PLC-γ1 as well) and the sustained phase of calcium response in B cells (6Scharenberg A.M. El-Hillal O. Fruman D.A. Beitz L.O. Li Z. Lin S. Gout I. Cantley L.C. Rawlings D.J. Kinet J.-P. EMBO J. 1998; 17: 1961-1972Crossref PubMed Scopus (386) Google Scholar, 7Fluckiger A.-C. Li Z. Kato R.M. Wahl M.I. Ochs H.D. Longnecker R. Kinet J.-P. Witte O.N. Scharenberg A.M. Rawlings D.J. EMBO J. 1998; 17: 1973-1985Crossref PubMed Scopus (358) Google Scholar,12Takata M. Kurosaki T. J. Exp. Med. 1996; 184: 31-40Crossref PubMed Scopus (426) Google Scholar). Another candidate target of Btk is BAP-135 (13Yang W. Desiderio S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 604-609Crossref PubMed Scopus (159) Google Scholar), a protein of unknown function, and Btk also regulates stress-activated protein kinases, JNK and p38, in mast cells (14Kawakami Y. Miura T. Bissonnette R. Hata D. Khan W.N. Kitamura T. Maeda-Yamamoto M. Hartman S.E. Yao L. Alt F.W. Kawakami T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3938-3942Crossref PubMed Scopus (128) Google Scholar). The PH domain is a protein module composed of loosely conserved sequences of ∼100 amino acid residues (15Haslam R.J. Koide H.B. Hemmings B.A. Nature. 1993; 363: 309-310Crossref PubMed Scopus (387) Google Scholar, 16Mayer B.J. Ren R. Clark K.L. Baltimore D. Cell. 1993; 73: 629-630Abstract Full Text PDF PubMed Scopus (380) Google Scholar), which are found in numerous signal-transducing and cytoskeletal proteins (reviewed in Refs. 17Musacchio A. Gibson T. Rice P. Thompson J. Saraste M. Trends Biochem. 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PH domains also by and of proteins as 31-40Crossref PubMed Scopus Google Scholar). Wild-type proteins in this as follows: for residues of and In the portion was from the oxysterol-binding protein PH domain by with by with and to the In vitro binding was as L. H. K. J. C. H. Kawakami Y. Kawakami T. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). proteins with mast cell in in the or of and by with or In proteins a from binding was also as L. Kawakami Y. Kawakami T. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). proteins by and with actin from or to and J.A. S. J. Biol. Chem. Full Text PDF PubMed Google Scholar) in and actin was by with was in P. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar) and at for with proteins or PH domains for and at for the and in by by or of Btk and cells with of the or in the Kawakami Y. H. H. G. A. Kato T. Y. Kawakami T. Biochem. 1993; PubMed Scopus Google Scholar). in by with was by in of actin the in of actin filaments. was initiated by the of and to of 3 and of PH domain proteins in A The was with a as a of of and at The and the of of containing F-actin and of PH domains a with a in a and the of at was by of a of and in of to the of the containing 3 and PH domain or in containing and and by the with the and with in and the in a at mast cells as a in with and with IgE and with of for the with and with by as as cells with a marrow-derived mast cells in and by FcεRI with IgE and as T. M. H. K.M. K. T. J. Immunol. Google Scholar). One proteins in by of mast cells and was as Y. Yao L. S. Witte O.N. Kawakami T. Cell. Biol. 1994; 14: PubMed Google Scholar). and Btk proteins in cells a to the was by the site of the a and the Btk has a peptide in of the Btk proteins by with or or by affinity with FcεRI cytoskeletal by increased F-actin membrane increased cell and and the of actin J. Biol. 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In order to the Btk protein in mast cells these mast cells with which a Btk in of cell that Btk has a in the in cells. upon FcεRI cross-linking, of F-actin with that a portion of the Btk protein is with F-actin in a co-localization stimulation the membrane the of the cells and for at at the of actin co-localization with Btk The that Btk may interact with vivo. was by from cells Btk proteins. was with antibody from of cells or Btk These data that actin or with Btk and that the kinase activity of Btk is for this In order to the molecular basis for the domains of Btk and other proteins bind to proteins containing the PH domains of Btk or with mast cell to these proteins by and by The protein of the PH domain a protein of The binding of the protein to was to a high The of this protein in from from the protein by The of this protein as actin was demonstrated by of proteins to or with antibody 3 actin in In several other PH domains 3 binding of to actin was whereas containing the N-terminal portion of the PH domain of bind to In or bind actin in the B and data These indicate that a subset of PH domains bind to the interaction between actin and PH domains is or not. actin was in of mast cell in a affinity or from was with actin and with and actin was with with that the interaction between actin and PH domains the of other proteins. Another to the interaction between PH domains and actin was to the actin-binding capacity of PH domains. proteins from signaling proteins by and with and actin was In this binding 3 C and the data in actin binding with the PH domains from and pleckstrin and C-terminal PH PH domains from PH or PH bind to The PH domain a binding The actin-binding site was mapped the PH domain of Btk. binding and mutated proteins and the data in 4 A. Since actin-binding proteins interact with actin via their with of residues with The that the amino acid sequence residues is a actin-binding stretch in which the residues in the domain The of the residues in this stretch is also in the of actin binding capacity in the PH domains that the from and 4 several PH domains of in which residues the β shown in the PH domain with was for actin whereas the other with at or or with at and to actin binding The of a with the PH domain the of the residues in binding to The data or the or the F-actin as the PH domain two to which of actin binds PH domains. a of actin and or in PH domain proteins with whereas of these proteins with In with vitro binding with F-actin whereas not. and proteins that from by also with F-actin In of of actin with or proteins in by polyacrylamide gel electrophoresis by of the proteins complexes with of PH domain with F-actin a of actin and of of to the binding was of to molecules of actin of and proteins that the for this interaction was was by of protein from the affinity of be that of the in vitro binding These are to of actin-binding proteins T. R. to the and Scholar). Since the and also mapped the N-terminal portion of PH domains M. Macias M.J. Nilges M. Oschkinat H. Saraste M. Wilmanns M. EMBO J. 1995; 14: 4676-4685Crossref PubMed Scopus (306) Google Scholar, 27Hyvonen M. Saraste M. EMBO J. 1997; 16: 3396-3404Crossref PubMed Scopus (193) Google Scholar, Hajduk P.J. H.S. Fesik S.W. Nature. 1994; PubMed Scopus Google Scholar, M. T. H. K. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google L. H. K. J. C. H. Kawakami Y. Kawakami T. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), binding to these molecules with the capacity of the PH domain to bind to and The of in the of actin and the actin with in a with of is with the that of Btk with M. Saraste M. EMBO J. 1997; 16: 3396-3404Crossref PubMed Scopus (193) Google Scholar). Phosphatidylinositol also a the a at the the other including and to the actin binding of was with mast cell in the of of in the of found The of of to the of and actin the of actin These data that the interaction of PH domains with actin is by studies have demonstrated in the PH domain as the binding of Btk for actin 4 for L. H. K. J. C. H. Kawakami Y. Kawakami T. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). actin have the binding of to as from the that binds to the C-terminal and sequences bind to have that PH domains have binding for these binding molecules in a short stretch of the of PH domains actin by and Since a of PH domain that from by with A that the PH domain the of actin the of it is at a high to actin of The in is with the of filament that the PH domain actin filament bundle as shown The data shown in the that the PH domain actin or the of actin filaments. The of actin was also by the PH with a of binding or filament R.P. R.P. Biochem. PubMed Scopus Google Scholar) in which was to F-actin with or PH domains that of actin in The of binding also that the binding of the PH domain the filament in a that interaction with that the of the structures formed by actin in the of the PH domain at of the PH domain in by the PH domain at to actin as as that the PH domain actin filament bundle and these of actin by The that is increased by the PH domain in of and high that the activity of the PH domain to be and a of the of the PH by is by C the from The of the at of the PH domain that of in the of the PH of the Btk PH domain actin bundle also by shown in of of the PH domain as a protein a in from 3 whereas was with that the actin filament bundle is a of actin-binding PH domains. A actin bundle was with the PH that a the actin-binding site with the actin binding was by the in vitro binding protein the protein was for binding to the of actin in mast cell the Btk bind actin in the of proteins. affinity to a of with was with actin and proteins by that Btk molecules with with These with the of Btk with actin in cells that Btk with F-actin in vitro and in vivo. Btk is in the of The of Btk protein in the cytoskeleton increased upon FcεRI Btk to the cytoskeleton upon stimulation, a with a binding activity of the PH domain and with Btk co-localization with actin fibers in FcεRI-stimulated cells these a role of the Btk PH domain in the cytoskeletal of Btk FcεRI also the membrane translocation of Btk Y. Yao L. S. Witte O.N. Kawakami T. Cell. Biol. 1994; 14: PubMed Google Scholar) probably through the interaction of the Btk PH domain with (5Li Z. Wahl M.I. Eguinoa A. Stephens L.R. Hawkins P.T. Witte O.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13820-13825Crossref PubMed Scopus (187) Google Scholar, 6Scharenberg A.M. El-Hillal O. Fruman D.A. Beitz L.O. Li Z. Lin S. Gout I. Cantley L.C. Rawlings D.J. Kinet J.-P. EMBO J. 1998; 17: 1961-1972Crossref PubMed Scopus (386) Google Scholar, 7Fluckiger A.-C. Li Z. Kato R.M. Wahl M.I. Ochs H.D. Longnecker R. Kinet J.-P. Witte O.N. Scharenberg A.M. Rawlings D.J. 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PubMed Scopus Google Scholar). PH domains of the residues this actin binding of the Btk PH domain by for the residues with and a of the N-terminal of the PH domain was by with for the residues in the β actin binding to be to these residues the PH domain and the PH domain have actin-binding the that PH domains have of residues in the actin-binding The the actin-binding region be for the interaction the actin-binding of the Btk PH and demonstrated actin filament of PH domains as or proteins. activity and the of a stretch for actin binding are shared by the M. A. A. Nature. PubMed Scopus Google Scholar). is a actin filament whereas which has phosphorylation the actin-binding not. phosphorylation from the plasma membrane to the molecules to have two actin-binding or to Since PH domain has this activity and the actin-binding site is mapped a 10-residue region of the Btk PH that PH domains have a activity with a actin-binding K. A. Cell. 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In Btk as a may have a filament of translocation of Btk to the actin cytoskeleton and actin filament activity it is that the cytoskeletal to FcεRI in and may be from that of The actin cytoskeleton plays a role in a of including cell and cell A of domain is their role in the of PH as shown for Btk in this PH as and are to with the these proteins their PH domains for the cytoskeletal other PH domain also to the activation by and in the of studies to the of molecular of the family in these activation of and to the of membrane and fibers and (reviewed in Refs. A. Trends Biol. 1996; Full Text PDF PubMed Scopus Google Scholar L. C. 1997; PubMed Scopus Google Scholar). The activity of this of which is from the to the is by and Nature. 1993; PubMed Scopus Google Scholar). of the regulatory proteins for the family proteins or two PH domains in their of the amino acid sequences of these PH domains that have actin binding capacity upon the of residues in their these PH domains bind actin in this capacity a role in these family regulatory proteins to the Btk regulates by the stress-activated protein kinases, upon FcεRI (14Kawakami Y. Miura T. Bissonnette R. Hata D. Khan W.N. Kitamura T. Maeda-Yamamoto M. Hartman S.E. Yao L. Alt F.W. Kawakami T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3938-3942Crossref PubMed Scopus (128) Google Scholar). it is that family which are to be involved in A. Biol. 1995; Scholar), are involved in signaling of Btk and of that regulates the activity of and other is that Btk is translocated to the actin cytoskeleton which Btk and candidate signal family and their to is actin is via of actin by binding of a PH domain to proteins as and filament is a numerous actin-binding proteins and in which PH domain-mediated and may for and M. and for their and actin
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