Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

Li, Wei; Cooper, Jonathan M.; Karajannis, Matthias A.; Giancotti, Filippo G.

doi:10.1038/embor.2012.11

Cited by 115 publications

(81 citation statements)

References 130 publications

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“…However, this difference was not significant in platinum-treated or overall patient cohort analyses. Together, these results are not consistent with merlin as an ovarian cancer tumor suppressor [25]. …”

Section: Resultsmentioning

confidence: 82%

“…Merlin ( m oesin, e zrin, and r adixin- l ike protei n ), a product of the neurofibromatosis 2 (NF2) gene, is typically thought of as a tumor suppressor and inherited NF2 mutations are associated with non-malignant central nervous system tumors [24]. Merlin does not possess intrinsic enzymatic activity and, in general, acts as a linker between the plasma membrane and the cytoskeleton affecting cell motility and signal transduction [25]. Moreover, merlin may inhibit FAK by interfering with integrin signaling [26].…”

Section: Introductionmentioning

confidence: 99%

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Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer

Shah¹,

Tancioni²,

Ward³

et al. 2014

Gynecologic Oncology

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Objective Focal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined. Methods Nine human and two murine ovarian cancer cell lines were analyzed for growth in the presence of a small molecule FAK inhibitor (PF-271, 0.1 to 1 μM) for 72 h. Merlin was evaluated by immunoblotting and immunostaining of a human ovarian tumor tissue array. Growth of cells was analyzed in an orthotopic tumor model and evaluated in vitro after stable shRNA-mediated merlin knockdown. Results Greater than 50% inhibition of OVCAR8, HEY and ID8-IP ovarian carcinoma cell growth occurred with 0.1 μM PF-271 in anchorage-independent (p<0.001) but not in adherent culture conditions. PF-271-mediated reduction in FAK Y397 phosphorylation occurred independently of growth inhibition. Suspended growth of OVCAR3, OVCAR10, IGROV1, IGROV1-IP, SKOV3, SKOV3-IP, A2780, and 5009-MOVCAR was not affected by 0.1 μM PF-271. Merlin expression did not correlate with serous ovarian tumor grade or stage. PF-271 (30 mg/kg, BID) did not inhibit 5009-MOVCAR tumor growth and merlin knockdown in SKOV3-IP and OVCAR10 cells did not alter suspended cell growth upon PF-271 addition. Conclusions Differential responsiveness to FAK inhibitor treatment were observed. Intrinsic low merlin protein levels correlated with PF-271-mediated anchorage-independent growth inhibition, but reduction in merlin expression did not induce sensitivity to FAK inhibition. Merlin levels may be useful for patient stratification in FAK inhibitor trials.

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Section: Resultsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer

Shah¹,

Tancioni²,

Ward³

et al. 2014

Gynecologic Oncology

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“…FAK has been demonstrated to play a role in proliferation, migration and survival of NF2 −/− schwannoma cells through activation of PI3K/AKT and ERK signaling pathways (9). Ectopic expression of Merlin in NF2 −/− MPM cells inhibited invasion, decreased FAK Tyr397 phosphorylation and impaired FAK interaction with its binding partners Src and p85 (26).…”

Section: Discussionmentioning

confidence: 99%

“…Merlin mediates tumor suppression and cell contact inhibition through reduction of Rac-PAK, mTORC1, Hippo, EGFR and FAK-Src signaling (9). Merlin localizes to cell-cell boundaries where it plays a role in the maturation of adherens junctions (10, 11).…”

Section: Introductionmentioning

confidence: 99%

Merlin Deficiency Predicts FAK Inhibitor Sensitivity: A Synthetic Lethal Relationship

et al. 2014

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The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition are deficient in the expression of the NF2 tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell-extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlin-negative MPM cells lead to their greater dependence on cell-ECM-induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated ALDH as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response due to reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment.

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“…Merlin is a multifunctional protein, which shuttles between the cell cortex and the nucleus in a manner reminiscent of the cell adhesion and signaling component β-catenin. However, it remains unclear if Merlin suppresses tumorigenesis by activating anti-mitogenic signals at the cell cortex or in the nucleus and by what molecular mechanism (Li et al , 2012; and references therein).…”

Section: Introductionmentioning

confidence: 99%

Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus

Cooper

Zhou³

et al. 2014

Cancer Cell

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196

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It is currently unclear if Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at the plasma membrane or by inhibiting the E3 ubiquitin ligase CRL4DCAF1 in the nucleus. We found that de-repressed CRL4DCAF1 promotes YAP and TEAD-dependent transcription by ubiquitylating and thereby inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2 mutant tumors. We conclude that de-repressed CRL4DCAF1 promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.

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Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

Cited by 115 publications

References 130 publications

Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer

Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer

Merlin Deficiency Predicts FAK Inhibitor Sensitivity: A Synthetic Lethal Relationship

Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus

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