Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4 DCAF1 to suppress oncogenic gene expression

Jonathan Cooper, Wei Li, Liru You, Gaia Schiavon, Angela Pepe-Caprio, Lu Zhou, Ryohei Ishii, Marco Giovannini, C. Oliver Hanemann, Stephen B. Long, Hediye Erdjument-Bromage, Pengbo Zhou, Paul Tempst, Filippo G. Giancotti

Research output: Contribution to journalArticle

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Abstract

Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain - containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubiquitin ligase CRL 4DCAF1 to suppress its activity. Depletion of DCAF1 blocks the hyperproliferation caused by inactivation of Merlin. Conversely, expression of a Merlin-insensitive DCAF1 mutant counteracts the antimitogenic effect of Merlin. Expression of Merlin or silencing of DCAF1 in Nf2-deficient cells induce an overlapping, tumor-suppressive program of gene expression. Mutations present in some tumors from NF2 patients disrupt Merlin's ability to interact with or inhibit CRL 4DCAF1. Lastly, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells isolated from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. Current studies are aimed at identifying the substrates and mechanism of action of CRL 4DCAF1 and examining its role in NF2-dependent tumorigenesis in mouse models. We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4 DCAF1.

Original languageEnglish (US)
Article numberpt6
JournalScience signaling
Volume4
Issue number188
DOIs
StatePublished - Aug 30 2011

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Neurofibromin 2
Neurofibromatosis 2
Ubiquitin-Protein Ligases
Gene expression
Gene Expression
Tumors
p21-Activated Kinases
Carcinogenesis
oleoyl-estrone
Contact Inhibition
Phosphorylation
Neurilemmoma
Cell proliferation
Cadherins
Cell membranes
Tumor Cell Line
Tumor Suppressor Genes
Integrins
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cooper, Jonathan ; Li, Wei ; You, Liru ; Schiavon, Gaia ; Pepe-Caprio, Angela ; Zhou, Lu ; Ishii, Ryohei ; Giovannini, Marco ; Hanemann, C. Oliver ; Long, Stephen B. ; Erdjument-Bromage, Hediye ; Zhou, Pengbo ; Tempst, Paul ; Giancotti, Filippo G. / Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4 DCAF1 to suppress oncogenic gene expression. In: Science signaling. 2011 ; Vol. 4, No. 188.
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title = "Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4 DCAF1 to suppress oncogenic gene expression",
abstract = "Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain - containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubiquitin ligase CRL 4DCAF1 to suppress its activity. Depletion of DCAF1 blocks the hyperproliferation caused by inactivation of Merlin. Conversely, expression of a Merlin-insensitive DCAF1 mutant counteracts the antimitogenic effect of Merlin. Expression of Merlin or silencing of DCAF1 in Nf2-deficient cells induce an overlapping, tumor-suppressive program of gene expression. Mutations present in some tumors from NF2 patients disrupt Merlin's ability to interact with or inhibit CRL 4DCAF1. Lastly, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells isolated from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. Current studies are aimed at identifying the substrates and mechanism of action of CRL 4DCAF1 and examining its role in NF2-dependent tumorigenesis in mouse models. We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4 DCAF1.",
author = "Jonathan Cooper and Wei Li and Liru You and Gaia Schiavon and Angela Pepe-Caprio and Lu Zhou and Ryohei Ishii and Marco Giovannini and Hanemann, {C. Oliver} and Long, {Stephen B.} and Hediye Erdjument-Bromage and Pengbo Zhou and Paul Tempst and Giancotti, {Filippo G.}",
year = "2011",
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doi = "10.1126/scisignal.2002314",
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Cooper, J, Li, W, You, L, Schiavon, G, Pepe-Caprio, A, Zhou, L, Ishii, R, Giovannini, M, Hanemann, CO, Long, SB, Erdjument-Bromage, H, Zhou, P, Tempst, P & Giancotti, FG 2011, 'Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4 DCAF1 to suppress oncogenic gene expression', Science signaling, vol. 4, no. 188, pt6. https://doi.org/10.1126/scisignal.2002314

Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4 DCAF1 to suppress oncogenic gene expression. / Cooper, Jonathan; Li, Wei; You, Liru; Schiavon, Gaia; Pepe-Caprio, Angela; Zhou, Lu; Ishii, Ryohei; Giovannini, Marco; Hanemann, C. Oliver; Long, Stephen B.; Erdjument-Bromage, Hediye; Zhou, Pengbo; Tempst, Paul; Giancotti, Filippo G.

In: Science signaling, Vol. 4, No. 188, pt6, 30.08.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4 DCAF1 to suppress oncogenic gene expression

AU - Cooper, Jonathan

AU - Li, Wei

AU - You, Liru

AU - Schiavon, Gaia

AU - Pepe-Caprio, Angela

AU - Zhou, Lu

AU - Ishii, Ryohei

AU - Giovannini, Marco

AU - Hanemann, C. Oliver

AU - Long, Stephen B.

AU - Erdjument-Bromage, Hediye

AU - Zhou, Pengbo

AU - Tempst, Paul

AU - Giancotti, Filippo G.

PY - 2011/8/30

Y1 - 2011/8/30

N2 - Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain - containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubiquitin ligase CRL 4DCAF1 to suppress its activity. Depletion of DCAF1 blocks the hyperproliferation caused by inactivation of Merlin. Conversely, expression of a Merlin-insensitive DCAF1 mutant counteracts the antimitogenic effect of Merlin. Expression of Merlin or silencing of DCAF1 in Nf2-deficient cells induce an overlapping, tumor-suppressive program of gene expression. Mutations present in some tumors from NF2 patients disrupt Merlin's ability to interact with or inhibit CRL 4DCAF1. Lastly, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells isolated from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. Current studies are aimed at identifying the substrates and mechanism of action of CRL 4DCAF1 and examining its role in NF2-dependent tumorigenesis in mouse models. We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4 DCAF1.

AB - Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain - containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubiquitin ligase CRL 4DCAF1 to suppress its activity. Depletion of DCAF1 blocks the hyperproliferation caused by inactivation of Merlin. Conversely, expression of a Merlin-insensitive DCAF1 mutant counteracts the antimitogenic effect of Merlin. Expression of Merlin or silencing of DCAF1 in Nf2-deficient cells induce an overlapping, tumor-suppressive program of gene expression. Mutations present in some tumors from NF2 patients disrupt Merlin's ability to interact with or inhibit CRL 4DCAF1. Lastly, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells isolated from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. Current studies are aimed at identifying the substrates and mechanism of action of CRL 4DCAF1 and examining its role in NF2-dependent tumorigenesis in mouse models. We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4 DCAF1.

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