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Review
. 2012 Mar;13(3):204-15.
doi: 10.1038/embor.2012.11.

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

Wei Li  1 , Jonathan Cooper, Matthias A Karajannis, Filippo G Giancotti
Affiliations
Review

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

Wei Li et al. EMBO Rep. 2012 Mar.

Abstract

Inhibition of proliferation by cell-to-cell contact is essential for tissue organization, and its disruption contributes to tumorigenesis. The FERM domain protein Merlin, encoded by the NF2 tumour suppressor gene, is an important mediator of contact inhibition. Merlin was thought to inhibit mitogenic signalling and activate the Hippo pathway by interacting with diverse target-effectors at or near the plasma membrane. However, recent studies highlight that Merlin pleiotropically affects signalling by migrating into the nucleus and inducing a growth-suppressive programme of gene expression through its direct inhibition of the CRL4DCAF1 E3 ubiquitin ligase. In addition, Merlin promotes the establishment of epithelial adhesion and polarity by recruiting Par3 and aPKC to E-cadherin-dependent junctions, and by ensuring the assembly of tight junctions. These recent advances suggest that Merlin acts at the cell cortex and in the nucleus in a similar, albeit antithetic, manner to the oncogene β-catenin.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Merlin and ERM protein domain organization and phosphoregulation.
(A) Merlin and other canonical ERM proteins have similar domain organizations consisting of an amino-terminal (N-term) FERM domain that is divided into three subdomains, an α-helical coiled-coil domain and a carboxy-terminal (C-term) hydrophilic tail. Canonical ERM proteins contain an actin-binding C-terminal ERM-associated domain (C-ERMAD; pink), whereas Merlin does not. It also has an extended N-terminal motif (green) unique among ERM proteins, illustrating its divergent structure with respect to other ERM proteins. Merlin phosphorylation sites are indicated. (B) Canonical ERM proteins are maintained in an inactive state by intramolecular interaction between the C-terminal tail and FERM domain. Phosphorylation of a C-terminal threonine by Rho kinase—which might be aided by ERM protein recruitment to membrane regions rich in phosphatidylinositol 4,5-bisphosphate—activates the protein by disrupting the head-to-tail interaction. (C) Conversely, Merlin's dephosphorylated and closed form is active and functions in tumour suppression and contact inhibition. Phosphorylation by PAK and PKA at Ser 518 renders the protein inactive in its putatively open form. ERM, Ezrin/Radixin/Moesin; FERM, 4.1 protein/Ezrin/Radixin/Moesin; MYPT1, myosin phosphatase targeting subunit 1; PAK, p21-activated kinase; PKA, protein kinase A; PIP2, phosphatidylinositol 4,5-bisphosphate; RhoK, Ras homologue gene family, member K.
Figure 2
Figure 2. Merlin missense mutations and single residue deletions in NF2.
The position, frequency and type of mutation are plotted on a schematic diagram of Merlin. The pathogenicity of mutations supported by biological evidence is shown in orange, by genetic evidence in blue and by both biological and genetic evidence in green. These mutations either correlate with disease in multiple members of a family, are found in two or more unrelated patients and/or there is biological evidence of their pathogenicity. Data were obtained from Ahronowitz et al, 2007 [18] and Li et al, 2010 [35]. FERM, 4.1 protein/Ezrin/Radixin/Moesin.
Figure 3
Figure 3. Merlin activation and downstream signalling.
The convergence of several upstream adhesion receptors regulates Merlin (Mer) activation and subsequently controls downstream mitogenic pathways. (A) The assembly of cell-to-cell adhesions and CD44 activation by hyaluronic-acid-rich matrix activates MYPT1, which dephosphorylates Merlin Ser 518 and maintains it in a closed and active conformation. Conversely, in sparse cells exposed to growth factors, integrins and receptor tyrosine kinases activate PAK, phosphorylating Ser 518. PKA—activated by increased cAMP—also phosphorylates Ser 518. (B) Merlin can affect a variety of mitogenic signalling pathways, including Rac–PAK signalling, mTORC1, EGFR–Ras–ERK and the PI3K–Akt pathway. In addition, Merlin contributes to the activation of the Hippo tumour-suppressor pathway. The active form of Merlin can enter the nucleus, bind to and inactivate the E3 ubiquitin ligase CRL4DCAF1. Akt, protein kinase B; cAMP, cyclic AMP; CRL4, cullin-ring E3 ligase 4; DCAF1, DDB1- and CUL4-associated factor 1; EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase; mTORC1, mammalian target of Rapamycin complex 1; MYPT1, myosin phosphatase targeting subunit 1; PAK, p21-activated kinase; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; Rac, Ras-related C3 botulinum toxin substrate; Ras, rat sarcoma.
Figure 4
Figure 4. Emerging mechanisms of Merlin-mediated epithelial adhesion, polarity and inhibition of proliferation.
(A) Merlin (Mer) is recruited to nascent adherens junctions by α-catenin and contributes to the activation of Hippo signalling by cooperating with Kibra to activate the classical core kinase cascade, or by enabling α-catenin to sequester phosphorylated YAP in the cytoplasm through 14-3-3 proteins. (B) Upon assembly of tight junctions, Merlin binds to Angiomotin and displaces the Rac GAP Rich, thereby inhibiting Rac. In addition, Merlin might assist Angiomotin in coordinating the activation of the Hippo core kinase cascade. (C) Engagement of E-cadherin or loss of integrin-mediated adhesion leads to inactivation of PAK, promoting an accumulation of the de-phosphorylated (active) form of Merlin. Active Merlin enters the nucleus and inhibits the E3 ubiquitin ligase CRL4DCAF1, thereby suppressing the expression of multiple pro-oncogenic genes. CRL4, cullin-ring E3 ligase 4; DCAF1, DDB1- and CUL4-associated factor 1; ERK, extracellular-signal-regulated kinase; LATS1/2, large tumour suppressor 1/2; Mst1/2, macrophage stimulating 1/2; PAK, p21-activated kinase; PALS1, protein associated with Lin-7 1; PATJ, Pals1-associated tight junction protein; Rac, Ras-related C3 botulinum toxin substrate; TEAD, TEA domain family member; YAP, Yes-associated protein.
None
Jonathan Cooper, Filippo G. Giancotti & Wei Li
None
Matthias A. Karajannis
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