Characterization of the β-Dystroglycan–Growth Factor Receptor 2 (Grb2) Interaction

Russo, Katia; Stasio, Enrico Di; Macchia, Gianfranco; Rosa, Giuseppina La; Brancaccio, Andrea; Petrucci, Tamara C.

doi:10.1006/bbrc.2000.3103

Cited by 80 publications

(69 citation statements)

References 37 publications

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“…Taken together, these findings support the hypothesis that increasing b-DG is per se able to reduce the growth and tumorigenicity of cancer cells independently of an increase in the a-DG-associated signaling transduction pathway. Indeed, b-DG can bind Grb2 (Yang et al, 1995;Russo et al, 2000), the growth factor receptor bound adapter protein involved in the activation of several signaling pathways (Chardin et al, 1995). Thus, an excess of b-DG might inhibit proliferation not only by a direct effect (i.e., activating inhibitory signals) but also by an indirect effect blocking or interfering with stimulatory signals (i.e., sequestering Grb2 and inhibiting activation of Grb2-dependent signaling pathways).…”

Section: Discussionmentioning

confidence: 99%

“…The transmembrane b-DG anchors a-DG to the cell membrane and is linked to the actin cytoskeleton via dystrophin or its paralogue utrophin (Ibraghimov-Beskrovnaya et al, 1992Winder, 2001). It also binds a variety of other cytoskeletal or cytosolic protein factors and the presence of a consensus sequence for Tyr phosphorylation suggests a potential involvement in signaling transduction pathways in a manner similar to integrins (Ervasti and Campbell, 1996;Cavaldesi et al, 1999;Russo et al, 2000;Winder, 2001;Chockalingam et al, 2002;Langenbach and Rando, 2002;Spence et al, 2004).…”

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confidence: 99%

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Dystroglycan expression is reduced during prostate tumorigenesis and is regulated by androgens in prostate cancer cells

Sgambato

Paola

Migaldi

et al. 2007

Journal Cellular Physiology

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Prostate cancer, the most frequently diagnosed cancer in Western men, can display a high variability in term of clinical aggressiveness and prognosis and none of the available markers is able to accurately predict its clinical course. Dystroglycan (DG), a non-integrin adhesion molecule, is a complex formed by two subunits, a-and b-DG, which bind to extracellular matrix molecules and cytoskeleton, respectively. DG expression is frequently reduced in human cancers and has been related to tumor grade and aggressiveness. This study investigated the role of DG in human prostate tumorigenesis and its suitability as a prognostic marker. The expression level of extracellular a-DG subunit was frequently reduced in human prostate cancer cell lines and primary tumors and the percentage of positive tumor cells was significantly further decreased in vivo following androgen ablation therapy (median ¼ 1%) compared to pre-treatment samples (median ¼ 28%). A significant relationship was observed between a-DG staining on the post-treatment samples and tumor recurrence. A dose-and timedependent decrease of DG expression also occurred in human prostate cancer cells following treatment with the anti-androgen flutamide. Stable expression of an exogenous DG cDNA in the LNCaP human prostate carcinoma cell line resulted in a marked inhibition of both anchorage-dependent and independent growth and of the in vivo tumorigenicity. These findings confirm and extend previous evidence that disturbances in the function of the DG complex might contribute to the definition of the malignant behavior of prostate cancer cells and suggest that androgens might regulate DG expression in these cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Dystroglycan expression is reduced during prostate tumorigenesis and is regulated by androgens in prostate cancer cells

Sgambato

Paola

Migaldi

et al. 2007

Journal Cellular Physiology

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“…27 Dystroglycan (DG), a ubiquitously expressed integral membrane glycoprotein, links the ECM to the actin cytoskeleton, thus providing structural integrity and perhaps transducing signal, in a manner similar to integrins. 6,[28][29][30][31][32] It has been hypothesized that loss of DG expression might play an important role in tumor development by altering the interactions between cells and the surrounding matrix. 7,[10][11][12] From this point of view, DG might act as a tumor suppressor gene and its loss of function could influence the formation of strong contacts between basement membranes and the cytoskeleton of cells, thus favoring tumor development and invasiveness.…”

Section: Discussionmentioning

confidence: 99%

“…In preliminary studies, we observed differential effects on the cell cycle regulatory proteins cyclin D1 and p27 Kip1 in the DG-overexpressing derivatives of the MCF10F and MCF7 cells (unpublished results) which might further support the hypothesis that different mechanisms mediate the cell growth inhibition observed in the two cell lines analyzed. Indeed, βDG can bind Grb2, 29,41 the growth factor receptor bound adapter protein involved in the activation of several signaling pathways, including the recruitment to plasma membrane and subsequent activation of the Ras oncogene. 42 Thus, an excess of βDG might inhibit proliferation not only by a direct effect (i.e., activating inhibitory signals) but also by an indirect effect blocking or interfering with stimulatory signals (i.e., sequestering Grb2 and inhibiting activation of Grb2-dependent signaling pathways).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of dystroglycan inhibits the growth and tumorigenicity of human mammary epithelial cells

Sgambato¹,

Camerini²,

Faraglia³

et al. 2004

Cancer Biology & Therapy

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Dystroglycan (DG) is an adhesion molecule formed by two subunits, α (extracellular) and β (transmembrane) DG, which are codified by a single gene and form a continuous link from the extracellular matrix to the intracellular cytoskeleton. Reduction or loss of expression of DG has been observed in human cancer cell lines and primary tumors and has been suggested to promote tumor development and invasiveness.In this study, the human breast epithelial non-tumorigenic MCF10F and the breast cancer MCF7 cell lines were engineered to stably express an exogenous DG cDNA and the effects on the phenotype of both cell lines were evaluated. The MCF10F transfected cells displayed an increased expression of both DG subunits which was associated with inhibition of the anchorage-dependent growth, accumulation of cells in the G 0 /G 1 phase of the cell cycle and increased adhesion to a substratum. The MCF7 transfected cells were unable to restore α-DG despite an increased expression of the β-DG subunit. Anchoragedependent and independent growth and the in vivo tumorigenicity were reduced in these derivatives that also displayed a reduced adhesion to a substratum and were shown to release α-DG in the culture medium.These findings confirm and extend previous evidence that transformation of mammary epithelial cells is associated with loss of their ability to retain α-DG on the cell membrane. Moreover, they indicate that DG is involved in cell functions other than cell adhesion to the extracellular matrix, and that its loss of function might predispose to tumor progression by compromising regulatory controls over cell growth and proliferation.

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“…It binds dystroglycan with high affinity and competes with dystrophin for the binding site on dystroglycan (Russo et al, 2000). Via Grb2, dystroglycan can interact with the C -terminal domain of focal adhesion kinase (FAK) (Cavaldesi et al, 1999b).…”

Section: Grb2 and Fakmentioning

confidence: 99%

Review: Dystroglycan in the Nervous System

Samwald

2007

Nature Precedings

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Dystroglycan is part of a large complex of proteins, the dystrophin-glycoprotein complex, which has been implicated in the pathogenesis of muscular dystrophies for a long time. Besides muscular degeneration many patients manifest symptoms of neurological and cognitive dysfunction. Recent findings suggest that dystroglycan is implicated in brain development, synapse formation and plasticity, nerve-glia interactions and maintenance of the blood-brain barrier. Most research so far has focused on the functions of dystroglycan in muscle and neuromuscular junctions, while its role in the brain and interneuronal synapses has been neglected. This review will give an overview of the biochemistry of dystroglycan, its interaction with other proteins as well as its confirmed and hypothetical functions in the nervous system.

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Characterization of the β-Dystroglycan–Growth Factor Receptor 2 (Grb2) Interaction

Cited by 80 publications

References 37 publications

Dystroglycan expression is reduced during prostate tumorigenesis and is regulated by androgens in prostate cancer cells

Dystroglycan expression is reduced during prostate tumorigenesis and is regulated by androgens in prostate cancer cells

Increased expression of dystroglycan inhibits the growth and tumorigenicity of human mammary epithelial cells

Review: Dystroglycan in the Nervous System

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