The Pleckstrin Homology Domain of Human βIΣII Spectrin Is Targeted to the Plasma Membranein Vivo

Wang, Dengshun; Miller, Rehae; Shaw, Regina; Shaw, Gerry

doi:10.1006/bbrc.1996.1189

Cited by 56 publications

(37 citation statements)

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“…Each group contained 3 ± 4 dishes, and each experiment was performed three times. Mean number of foci/pmol DNA+standard deviation was calculated beta 1 sigma II spectrin (Wang et al, 1996), Sos (Chen et al, 1997) and b-adrenergic receptor kinase (Pitcher et al, 1995) data supports the model of the PH domain acting as a plasma membrane targeting module. However, in the case of the Dbl-homology protein family the role of the PH domains in subcellular localization is less clear.…”

Section: Resultsmentioning

confidence: 59%

Distinct roles for DH and PH domains in the Lbc oncogene

et al. 1997

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Members of the Dbl-homology (DH) family of proteins promote guanine nucleotide exchange on Rho GTPases. Lbc, which speci®cally acts on Rho but not Rac or Cdc42, was isolated as a transforming oncogene and is composed of a DH and a Pleckstrin-homology (PH) domain. We show here that the Lbc DH domain alone is capable of stimulating new DNA synthesis in quiescent ®broblasts and Rho-dependent actin stress ®ber assembly. However, the PH domain is required for subcellular localization of Lbc along actin stress ®bers and for ecient transformation of NIH3T3 cells. The results show that, in contrast to other Dbl-homology proteins, the PH domain of Lbc is dispensable for activation of Rho in vivo. The PH domain-dependent subcellular localization of Lbc may, however, be important for growth factor activation of endogenous Lbc and for oncogenic transformation.

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Section: Resultsmentioning

confidence: 59%

Distinct roles for DH and PH domains in the Lbc oncogene

et al. 1997

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“…As previously discussed, mounting biochemical evidence supports the hypothesis that PH domain containing proteins may be recruited to the plasma membrane via interaction with membrane proximal phospholipids or proteins (Hemmings, 1997;Harlan et al, 1994;Lemmon et al, 1995;Ferguson et al, 1995;Wang and Shaw, 1995;Salim et al, 1996;Fukuda et al, 1996;Wang et al, 1996;Touhara et al, 1994;Yao et al, 1994;Yenush et al, 1996). GagBtk proteins with PH domain mutations were used to determine if the Btk PH domain serves as essential signaling function in addition to membrane localization.…”

Section: The Ph Domain Is Not Required For Gagbtk Mediated Transformamentioning

confidence: 98%

“…The observation that the myristylated Gag sequences alleviate the requirement for the PH domain suggests that the PH domain serves to facilitate membrane association of Btk. This is supported by the ®nding that the spectrin PH domain is su cient to target a reporter gene to the plasma membrane (Wang et al, 1996). Several potential PH domain ligands are located at membrane proximal sites and may serve as docking sites for Btk.…”

Section: The Ph Domain As a Membrane Targeting Motifmentioning

confidence: 99%

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Constitutive membrane association potentiates activation of Bruton tyrosine kinase

Rawlings

Park

et al. 1997

Oncogene

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Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunode®ciencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunode®-ciency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk*) results in ®broblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is su cient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 ®broblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.

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“…Most ␤-Spectrin isoforms contain an actin-binding domain at their N termini, an Ankyrin-binding domain, and a pleckstrin homology (PH) domain near their C termini. The PH domain of ␤-Spectrin interacts with the plasma membrane in transfected COS cells (Wang et al, 1996). ␣-Spectrin contains an SH3 domain and two EF-hand motifs (Bennett and Baines, 2001).…”

Section: Introductionmentioning

confidence: 99%

β-Spectrin functions independently of Ankyrin to regulate the establishment and maintenance of axon connections in theDrosophilaembryonic CNS

et al. 2007

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DEVELOPMENT 273 RESEARCH ARTICLE INTRODUCTIONDuring central nervous system (CNS) development, growth cones navigate a series of choice points to find their appropriate targets. These guidance decisions are shaped by a balance of attractive and repulsive cues found in the extracellular environment that can act locally or at a distance (Tessier-Lavigne and Goodman, 1996). Slit ligands and Robo receptors play conserved roles in regulating midline axon crossing in both invertebrate and vertebrate nervous systems. In the Drosophila embryonic CNS, ipsilateral neurons (neurons that do not cross the midline) express the Robo receptor on their surface, which senses Slit to prevent midline crossing (Kidd et al., 1999;Kidd et al., 1998). By contrast, commissural neurons can overcome Slit repulsion because expression of Robo on their surface is prevented prior to midline crossing by the Commissureless (Comm) protein (Keleman et al., 2002). Thus, the specific receptors that a growth cone expresses as it encounters the midline greatly influences its guidance decision. The question of how guidance receptors and their downstream effectors are targeted to and distributed within functional domains of the growth cone plasma membrane remains key to the understanding of the mechanisms of axon path finding.The Spectrin molecule, a long rod-shaped heterotetramer consisting of two ␣ and two ␤ subunits, is the defining element of a ubiquitous sub-membrane cytoskeletal network in nearly all metazoan cells (Bennett and Baines, 2001). Most ␤-Spectrin isoforms contain an actin-binding domain at their N termini, an Ankyrin-binding domain, and a pleckstrin homology (PH) domain near their C termini. The PH domain of ␤-Spectrin interacts with the plasma membrane in transfected COS cells (Wang et al., 1996). ␣-Spectrin contains an SH3 domain and two EF-hand motifs (Bennett and Baines, 2001).In red blood cells, the Spectrin network was originally shown to have a role in supporting cell shape (Bennett and Chen, 2001); however, more recently it has been shown to participate in the formation of specialized membrane sub-domains (Bennett and Chen, 2001). Through its binding partner Ankyrin, the Spectrin network links many integral membrane proteins to the actin cytoskeleton. Genetic studies have revealed that many membrane proteins are mislocalized in the absence of Spectrin or Ankyrin (Dubreuil et al., 2000;Jenkins and Bennett, 2001;Komada and Soriano, 2002;Zhou et al., 1998). In addition, mutations in the vertebrate ␤-Spectrin and Ankyrin genes have been linked to various diseases, such as hereditary hemolytic anemias and spinocerebellar ataxia in humans, and auditory and motor neuropathies in mice (Ikeda et al., 2006;Mohler and Bennett, 2005;Parkinson et al., 2001). It has been proposed that Ankyrin and ␤-Spectrin are interdependent, and mutually stabilize the formation of polarized domains at axon initial segments and nodes of Ranvier (Komada and Soriano, 2002). Yet the relationship between Ankyrin and ␤-Spectrin, and the role that each plays in c...

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The Pleckstrin Homology Domain of Human βIΣII Spectrin Is Targeted to the Plasma Membranein Vivo

Cited by 56 publications

References 0 publications

Distinct roles for DH and PH domains in the Lbc oncogene

Distinct roles for DH and PH domains in the Lbc oncogene

Constitutive membrane association potentiates activation of Bruton tyrosine kinase

β-Spectrin functions independently of Ankyrin to regulate the establishment and maintenance of axon connections in theDrosophilaembryonic CNS

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