Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis

Robb, Victoria A.; Wen, Li; Gascard, Philippe; Perry, Arie; Mohandas, Narla; Gutmann, David H.

doi:10.1016/s0969-9961(03)00071-8

Cited by 75 publications

(63 citation statements)

References 67 publications

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“…Similar to merlin, Protein 4.1B has been shown to interact with CD44 (Morrison et al, 2001;Robb et al, 2003), a widely expressed cell surface hyaluronate receptor, and the cytoskeletal protein bII spectrin (Gutmann et al, 2001a;Gimm et al, 2002). In contrast, Protein 4.1B does not interact with other known merlin-interacting proteins, including SCHIP-1 and HRS (Gutmann et al, 2001a).…”

Section: Discussionmentioning

confidence: 99%

“…To provide insight into the mechanism(s) underlying Protein 4.1B growth suppression, efforts have focused on characterizing potential interacting proteins that might mediate the Protein 4.1B growth inhibitory signal. Protein 4.1B interacts with CD44 (Robb et al, 2003), bII-spectrin (Gutmann et al, 2001a;Gimm et al, 2002), 14-3-3 b, g, and Z , Protein arginine N-methyltransferase 3 (PRMT3, Robb et al, 2003;Singh et al, manuscript in preparation), and the membrane proteins Caspr/paranodin and Caspr2 (Denisenko-Nehrbass et al, 2003). In contrast, Protein 4.1B does not interact with several merlin-binding proteins, including schwannomin interacting protein-1 (SCHIP-1; Goutebroze et al, 2000) and hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), which has been implicated in merlin growth suppression (Scoles et al, 2000;Gutmann et al, 2001b;Scoles et al, 2002;Sun et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Disruption of 14-3-3 binding does not impair Protein 4.1B growth suppression

2004

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disruption of 14-3-3 binding does not impair Protein 4.1B growth suppression

2004

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“…For the in vitro binding experiments, GST fusion protein (GST) or GST fusion protein containing full-length HRS (HRS) were immobilized on glutathione and incubated with [ 35 S]methionine merlin containing either the S518A or S518D mutation using protocols operational in our laboratory (Sherman et al, 1997;Robb et al, 2003). Aliquots of the total radiolabeled protein and total eluted proteins were separated by SDS-PAGE and analysed by autoradiography.…”

Section: S518 Phosphomerlin Mutant Binding Experimentsmentioning

confidence: 99%

“…Aliquots of the total radiolabeled protein and total eluted proteins were separated by SDS-PAGE and analysed by autoradiography. For the in vivo binding experiments, His-tagged CD44 cytoplasmic tail and merlin mutants were cotransfected into RT4 rat schwannoma cells using Lipofectamine and harvested 48 h later as previously reported by our laboratory (Gutmann et al, 1999b;Robb et al, 2003). Proteins bound to His-CD44 were collected using Ni-NTA Agarose (Qiagen) and eluted for analysis by SDS-PAGE and Western blot with merlin antibodies.…”

Section: S518 Phosphomerlin Mutant Binding Experimentsmentioning

confidence: 99%

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Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression

et al. 2004

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The neurofibromatosis 2 (NF2) tumor suppressor protein, merlin, functions as a negative growth regulator; however, the molecular mechanisms that underlie merlin regulation remain elusive. Recent studies have implicated merlin phosphorylation in regulating merlin subcellular localization and growth suppression. P21-activated kinase (PAK), a downstream target of Rac1/Cdc42, directly phosphorylates merlin at Serine 518. In this report, we show that PAK2 directly phosphorylates wild-type merlin, whereas merlin truncation mutants with impaired GST-aminoterminal domain (N-term or NTD)/GST-carboxy-terminal domain (C-term or CTD) intramolecular association exhibit impaired S518 phosphorylation. We directly demonstrate that PAK2 phosphorylation impairs merlin N-term/C-term binding in vitro and in vivo. Lastly, we show that PAK2 phosphorylation impairs the ability of merlin to bind to two interacting proteins, CD44 and hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), both critical for merlin growth suppression. These observations suggest that merlin S518 phosphorylation directly modulates merlin intramolecular and intermolecular associations important for the ability of merlin to function as a tumor suppressor.

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Microarray‐based gene expression profiling of benign, atypical and anaplastic meningiomas identifies novel genes associated with meningioma progression

Wrobel

Roerig

Kokocinski

et al. 2004

Intl Journal of Cancer

130

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To identify gene expression profiles associated with human meningiomas of different World Health Organization (WHO) malignancy grades, we analyzed 30 tumors (13 benign meningiomas, WHO grade I; 12 atypical meningiomas, WHO grade II; 5 anaplastic meningiomas, WHO grade III) for the expression of 2,600 genes using cDNA-microarray technology. Receiver operator curve (ROC) analysis with a cutoff value of 45% selection probability identified 37 genes with decreased and 27 genes with increased expression in atypical and anaplastic meningiomas, compared to benign meningiomas. Supervised classification of the tumors did not reveal specific expression patterns representative of each WHO grade. However, anaplastic meningiomas could be distinguished from benign meningiomas by differential expression of a distinct set of genes, including several ones associated with cell cycle regulation and proliferation. Investigation of potential correlations between microarray expression data and genomic aberrations, detected by comparative genomic hybridization (CGH), demonstrated that losses on chromosomes 10 and 14 were associated with distinct expression profiles, including increased expression of several genes related to the insulin-like growth factor (IGF) (IGF2, IGFBP3 and AKT3) or wingless (WNT) (CTNNB1, CDK5R1, ENC1 and CCND1) pathways. Taken together, our microarray-based expression profiling revealed interesting novel candidate genes and pathways that may contribute to meningioma progression.

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Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis

Abstract: Meningiomas are common tumors of the central nervous system, however, the mechanisms underlying their pathogenesis are largely undefined. Two members of the Protein 4

Cited by 75 publications

References 67 publications

Disruption of 14-3-3 binding does not impair Protein 4.1B growth suppression

Disruption of 14-3-3 binding does not impair Protein 4.1B growth suppression

Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression

Microarray‐based gene expression profiling of benign, atypical and anaplastic meningiomas identifies novel genes associated with meningioma progression

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