A Clue to the Therapy of Neurofibromatosis Type 2

Hirokawa, Yumiko; Tikoo, Anjali; Huynh, John; Utermark, Tamara; Hanemann, C. Oliver; Giovannini, Marco; Xiao, Guang-Hui; Testa, Joseph R.; Wood, John L.; Miyata, Hiroshi

doi:10.1097/00130404-200401000-00006

Cited by 98 publications

(90 citation statements)

References 21 publications

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“…The inhibitory effect of merlin on FAK activity could be either direct, as merlin has been previously shown to form a complex with FAK and NHERF (James et al, 2004), or indirect through inhibition of Rac/PAK signaling, which is known to cross-talk with FAK signaling (Hsia et al, 2003;Brown et al, 2005;Mitra et al, 2005). Indeed, we and others have previously linked merlin to Rac/PAK signaling, as PAK was found to be able to phosphorylate and inactivate merlin (Kissil et al, 2002;Xiao et al, 2002) and unphosphorylated merlin has been shown to inhibit PAK activity (Kissil et al, 2003;Hirokawa et al, 2004;Xiao et al, 2005) and Rac translocation to matrix adhesions (Okada et al, 2005). PAK activity has been shown to affect cell motility and directionality (Sells et al, 1999).…”

Section: Discussionmentioning

confidence: 90%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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The neurofibromatosis type 2 NF2 gene product, merlin, is a tumor suppressor frequently inactivated in malignant mesothelioma (MM). To investigate a possible correlation between merlin inactivation and MM invasiveness, we restored merlin expression in NF2-deficient MM cells. Re-expression of merlin markedly inhibited cell motility, spreading and invasiveness, properties connected with the malignant phenotype of MM cells. To test directly whether merlin inactivation promotes invasion in a nonmalignant system, we used small interfering RNA to silence Nf2 in mouse embryonic fibroblasts (MEFs) and found that downregulation of merlin resulted in enhanced cell spreading and invasion. To delineate signaling events connected with this phenotype, we investigated the effect of merlin expression on focal adhesion kinase (FAK), a key component of cellular pathways affecting migration and invasion. Expression of merlin attenuated FAK phosphorylation at the critical phosphorylation site Tyr397 and disrupted the interaction of FAK with its binding partners Src and p85, the regulatory subunit of phosphatidylinositol-3-kinase. In addition, NF2-null MM cells stably overexpressing FAK showed increased invasiveness, which decreased significantly when merlin expression was restored. Collectively, these findings suggest that merlin inactivation is a critical step in MM pathogenesis and is related, at least in part, with upregulation of FAK activity.

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Section: Discussionmentioning

confidence: 90%

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

et al. 2006

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“…The recent studies by Kissil and co-workers have shown that merlin can also function to inhibit PAK activity (Kissil et al, 2003;Hirokawa et al, 2004), suggesting an intimate relationship between merlin and PAK, in which PAK can inhibit merlin function and merlin can, in turn, suppress PAK activity. This reciprocal regulation suggests that merlin growth suppression is a tightly regulated process, and that the target of merlin inhibition might also be involved in regulating merlin function.…”

Section: Discussionmentioning

confidence: 99%

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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“…We assessed additional motility regulators including Cdc42, Pak1, ROCK1 and ROCK2 (Klemke et al, 1998;Zhao et al, 2000;Kaempchen et al, 2003;Worthylake and Burridge, 2003;Hirokawa et al, 2004;Xiao et al, 2005) (Figure 4e-g). HEI10 depletion had no effect on the steady-state levels of Cdc42 or Pak1 and significantly decreased the levels of ROCK1 and ROCK2.…”

Section: Hei10 Is Required For Cell Proliferationmentioning

confidence: 99%

HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins

et al. 2007

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Human enhancer of invasion, clone 10 (HEI10) (CCNB1IP1) was first described as a RING-finger family ubiquitin ligase that regulates cell cycle by interacting with cyclin B and promoting its degradation. Subsequently, other studies suggested specific upregulation of HEI10 in metastatic melanoma and demonstrated direct interaction between HEI10 and the tumor suppressor Merlin, encoded by the neurofibromatosis 2 gene. These and other results led us to hypothesize that HEI10 also influences the processes of cell migration and metastasis. We here show that cells with depleted HEI10 both migrate more rapidly and invade more effectively than control cells. HEI10 depletion post-transcriptionally increases the expression of a group of promotility regulatory proteins including p130Cas, paxillin, Cdk1 and cyclin B2, but excluding Merlin. Among these, only inhibition of Cdk1/ cyclin B activity specifically reversed the motility and invasion of HEI10-depleted cells. Finally, HEI10 is abundantly transcribed in many human tissues, and particularly abundant in some tumor cell lines, suggesting that it may be commonly involved in coordinating cell cycle with cell migration and invasion.

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A Clue to the Therapy of Neurofibromatosis Type 2

Abstract: These results suggest that PAK1 is essential for the malignant growth of NF2-deficient cells, and that PAK1-blocking drugs could be potentially useful forthe treatment of neurofibromatosis types 2, in addition to Ras-induced cancers and neurofibromatosis type 1.

Cited by 98 publications

References 21 publications

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK

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

HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins

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