• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Oct 24, 1995; 92(22): 10282–10286.
PMCID: PMC40780

Abr and Bcr are multifunctional regulators of the Rho GTP-binding protein family.

Abstract

Philadelphia chromosome-positive leukemias result from the fusion of the BCR and ABL genes, which generates a functional chimeric molecule. The Abr protein is very similar to Bcr but lacks a structural domain which may influence its biological regulatory capabilities. Both Abr and Bcr have a GTPase-activating protein (GAP) domain similar to those found in other proteins that stimulate GTP hydrolysis by members of the Rho family of GTP-binding proteins, as well as a region of homology with the guanine nucleotide dissociation-stimulating domain of the DBL oncogene product. We purified as recombinant fusion proteins the GAP- and Dbl-homology domains of both Abr and Bcr. The Dbl-homology domains of Bcr and Abr were active in stimulating GTP binding to CDC42Hs, RhoA, Rac1, and Rac2 (rank order, CDC42Hs > RhoA > Rac1 = Rac2) but were inactive toward Rap1A and Ha-Ras. Both Bcr and Abr acted as GAPs for Rac1, Rac2, and CDC42Hs but were inactive toward RhoA, Rap1A, and Ha-Ras. Each individual domain bound in a noncompetitive manner to GTP-binding protein substrates. These data suggest the multifunctional Bcr and Abr proteins might interact simultaneously and/or sequentially with members of the Rho family to regulate and coordinate cellular signaling.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, de Klein A, Bartram CR, Grosveld G. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 1983 Nov 17;306(5940):239–242. [PubMed]
  • Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984 Jan;36(1):93–99. [PubMed]
  • Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985 Jun 13;315(6020):550–554. [PubMed]
  • Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G. Structural organization of the bcr gene and its role in the Ph' translocation. Nature. 315(6022):758–761. [PubMed]
  • Hermans A, Heisterkamp N, von Linden M, van Baal S, Meijer D, van der Plas D, Wiedemann LM, Groffen J, Bootsma D, Grosveld G. Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell. 1987 Oct 9;51(1):33–40. [PubMed]
  • Maru Y, Witte ON. The BCR gene encodes a novel serine/threonine kinase activity within a single exon. Cell. 1991 Nov 1;67(3):459–468. [PubMed]
  • Hart MJ, Eva A, Evans T, Aaronson SA, Cerione RA. Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product. Nature. 1991 Nov 28;354(6351):311–314. [PubMed]
  • Hart MJ, Eva A, Zangrilli D, Aaronson SA, Evans T, Cerione RA, Zheng Y. Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product. J Biol Chem. 1994 Jan 7;269(1):62–65. [PubMed]
  • Diekmann D, Brill S, Garrett MD, Totty N, Hsuan J, Monfries C, Hall C, Lim L, Hall A. Bcr encodes a GTPase-activating protein for p21rac. Nature. 1991 May 30;351(6325):400–402. [PubMed]
  • Fry MJ. Defining a new GAP family. Curr Biol. 1992 Feb;2(2):78–80. [PubMed]
  • Shou C, Farnsworth CL, Neel BG, Feig LA. Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21. Nature. 1992 Jul 23;358(6384):351–354. [PubMed]
  • Settleman J, Narasimhan V, Foster LC, Weinberg RA. Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus. Cell. 1992 May 1;69(3):539–549. [PubMed]
  • Settleman J, Albright CF, Foster LC, Weinberg RA. Association between GTPase activators for Rho and Ras families. Nature. 1992 Sep 10;359(6391):153–154. [PubMed]
  • Heisterkamp N, Morris C, Groffen J. ABR, an active BCR-related gene. Nucleic Acids Res. 1989 Nov 11;17(21):8821–8831. [PMC free article] [PubMed]
  • Heisterkamp N, Kaartinen V, van Soest S, Bokoch GM, Groffen J. Human ABR encodes a protein with GAPrac activity and homology to the DBL nucleotide exchange factor domain. J Biol Chem. 1993 Aug 15;268(23):16903–16906. [PubMed]
  • Hall A. Small GTP-binding proteins and the regulation of the actin cytoskeleton. Annu Rev Cell Biol. 1994;10:31–54. [PubMed]
  • Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992 Aug 7;70(3):401–410. [PubMed]
  • Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM. Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2. Science. 1991 Dec 6;254(5037):1512–1515. [PubMed]
  • Bokoch GM. Regulation of the human neutrophil NADPH oxidase by the Rac GTP-binding proteins. Curr Opin Cell Biol. 1994 Apr;6(2):212–218. [PubMed]
  • Voncken JW, van Schaick H, Kaartinen V, Deemer K, Coates T, Landing B, Pattengale P, Dorseuil O, Bokoch GM, Groffen J, et al. Increased neutrophil respiratory burst in bcr-null mutants. Cell. 1995 Mar 10;80(5):719–728. [PubMed]
  • Chuang TH, Xu X, Quilliam LA, Bokoch GM. SmgGDS stabilizes nucleotide-bound and -free forms of the Rac1 GTP-binding protein and stimulates GTP/GDP exchange through a substituted enzyme mechanism. Biochem J. 1994 Nov 1;303(Pt 3):761–767. [PMC free article] [PubMed]
  • Knaus UG, Heyworth PG, Kinsella BT, Curnutte JT, Bokoch GM. Purification and characterization of Rac 2. A cytosolic GTP-binding protein that regulates human neutrophil NADPH oxidase. J Biol Chem. 1992 Nov 25;267(33):23575–23582. [PubMed]
  • Xu X, Barry DC, Settleman J, Schwartz MA, Bokoch GM. Differing structural requirements for GTPase-activating protein responsiveness and NADPH oxidase activation by Rac. J Biol Chem. 1994 Sep 23;269(38):23569–23574. [PubMed]
  • Bokoch GM, Bohl BP, Chuang TH. Guanine nucleotide exchange regulates membrane translocation of Rac/Rho GTP-binding proteins. J Biol Chem. 1994 Dec 16;269(50):31674–31679. [PubMed]
  • Zheng Y, Bagrodia S, Cerione RA. Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. J Biol Chem. 1994 Jul 22;269(29):18727–18730. [PubMed]
  • Gulbins E, Coggeshall KM, Baier G, Katzav S, Burn P, Altman A. Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation. Science. 1993 May 7;260(5109):822–825. [PubMed]
  • Tan EC, Leung T, Manser E, Lim L. The human active breakpoint cluster region-related gene encodes a brain protein with homology to guanine nucleotide exchange proteins and GTPase-activating proteins. J Biol Chem. 1993 Dec 25;268(36):27291–27298. [PubMed]
  • Ridley AJ, Self AJ, Kasmi F, Paterson HF, Hall A, Marshall CJ, Ellis C. rho family GTPase activating proteins p190, bcr and rhoGAP show distinct specificities in vitro and in vivo. EMBO J. 1993 Dec 15;12(13):5151–5160. [PMC free article] [PubMed]
  • Nobes CD, Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell. 1995 Apr 7;81(1):53–62. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • Gene
    Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...