Merlin, a “Magic” Linker Between the Extracellular Cues and Intracellular Signaling Pathways that Regulate Cell Motility, Proliferation, and Survival

Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY10029, USA.
Current Protein and Peptide Science (Impact Factor: 3.15). 09/2010; 11(6):471-84. DOI: 10.2174/138920310791824011
Source: PubMed


Genetic alterations of neurofibromatosis type 2 (NF2) gene lead to the development of schwannomas, meningiomas, and ependymomas. Mutations of NF2 gene were also found in thyroid cancer, mesothelioma, and melanoma, suggesting that it functions as a tumor suppressor in a wide spectrum of cells. The product of NF2 gene is merlin (moesin-ezrin-radixin-like protein), a member of the Band 4.1 superfamily proteins. Merlin shares significant sequence homology with the ERM (Ezrin-Radixin-Moesin) family proteins and serves as a linker between transmembrane proteins and the actin-cytoskeleton. Merlin is a multifunctional protein and involved in integrating and regulating the extracellular cues and intracellular signaling pathways that control cell fate, shape, proliferation, survival, and motility. Recent studies showed that merlin regulates the cell-cell and cell-matrix adhesions and functions of the cell surface adhesion/extracellular matrix receptors including CD44 and that merlin and CD44 antagonize each other's function and work upstream of the mammalian Hippo signaling pathway. Furthermore, merlin plays important roles in stabilizing the contact inhibition of proliferation and in regulating activities of several receptor tyrosine kinases. Accumulating data also suggested an emerging role of merlin as a negative regulator of growth and progression of several non-NF2 associated cancer types. Together, these recent advances have improved our basic understanding about merlin function, its regulation, and the major signaling pathways regulated by merlin and provided the foundation for future translation of these findings into the clinic for patients bearing the cancers in which merlin function and/or its downstream signaling pathways are impaired or altered.

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    • "Several extracellular cues are dependent on the interaction of ERM proteins with the CD44 ICD for their signaling, and these interactions serve to integrate some of these signals. The ERM-related protein merlin (Trofatter et al., 1993) is a tumor suppressor that is encoded by the neurofibromatosis-2 gene (NF2) and interacts with the CD44 ICD (Stamenkovic & Yu, 2010). Increased expression of merlin suppresses schwannoma cell growth (Bai et al., 2007; Morrison et al., 2001), but only at high cell density (Bai et al., 2007; Morrison et al., 2001) and requires the interaction between merlin and CD44 (Bai et al., 2007). "
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    ABSTRACT: The reception and integration of the plethora of signals a cell receives from its microenvironment is decisive in determining cell behavior. Perturbation of extracellular cues, or an inappropriate response to or integration of these signals lies at the root of many diseases such as cancer. The transmembrane protein CD44 contributes to the reception of a broad variety of microenvironmental components, including extracellular matrix constituents such as hyaluronic acid, as well as growth factors and cytokines. In this chapter, we review the range of extracellular cues that are recognized by CD44, and show how CD44 serves to integrate this information at several levels through the mechanisms by which it contributes to transduction of these various microenvironmental signals.
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    • "It exists in ten isoforms, with isoform-1 and −2 being the most common. All isoforms possess an N-terminal part, which contains the four point one Erzin-Radixin-Moezin (FERM) domain, followed by an alpha-helical domain, and a hydrophilic tail [18]. Merlin is involved in the control of various aspects of the cell cycle and the tumorigenesis (Fig. 1) [4] [19] [20]. "
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    ABSTRACT: Merlin, a tumor suppressor protein, controls essential steps of cell cycle, and its deficiency results in cellular overgrowth, proliferation, angiogenesis, invasion and metastasis. Lack of Merlin is responsible for neurofibromatosis-2, most schwannomas, and many meningiomas and ependymomas. We hypothesize that there is a role for statins to ameliorate Merlin's deficiency in this set of tumors by inhibiting a number of Merlin's downstream effectors, the small Rho-GTP-ases, and we present the relevant data. The ultimate goal is to offer a medical therapy promising to halt or reduce the tumor growth-rate in patients harboring Merlin-deficient neoplasms and to provide an adjuvant systemic therapy for patients undergoing stereotactic radio-surgery and partial tumor resection.
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    • "In the above papers, it was hypothesized that members of the ERM (ezrin, radixin, moesin) family of adapter proteins could be the probable physical linkers of the NHE1 to the invadopodia actin cytoskeleton since one of the members, ezrin, has been shown to bind to both NHE1 and F-actin and to participate in their reciprocal regulation [12-14]. Ezrin contains an N-terminal domain that recruits a variety of membrane receptors/transporters and a C-terminal domain termed the COOH-terminal ERM-associated domain (C-ERMAD) that binds to the actin cytoskeleton, characteristics which create functional complexes that regulate many processes [15,16], including cell proliferation, survival and apoptosis [17], migration [17,18], spatiotemporal control of various signaling molecules including cAMP [19] and the formation of microvilli [20-22]. "
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    ABSTRACT: Extracellular matrix (ECM) degradation is a critical process in tumor cell invasion and requires matrix degrading protrusions called invadopodia. The Na(+)/H(+) exchanger (NHE1) has recently been shown to be fundamental in the regulation of invadopodia actin cytoskeleton dynamics and activity. However, the structural link between the invadopodia cytoskeleton and NHE1 is still unknown. A candidate could be ezrin, a linker between the NHE1 and the actin cytoskeleton known to play a pivotal role in invasion and metastasis. However, the mechanistic basis for its role remains unknown. Here, we demonstrate that ezrin phosphorylated at T567 is highly overexpressed in the membrane of human breast tumors and positively associated with invasive growth and HER2 overexpression. Further, in the metastatic cell line, MDA-MB-231, p-ezrin was almost exclusively expressed in invadopodia lipid rafts where it co-localized in a functional complex with NHE1, EGFR, ß1-integrin and phosphorylated-NHERF1. Manipulation by mutation of ezrins T567 phosphorylation state and/or PIP2 binding capacity or of NHE1s binding to ezrin or PIP2 demonstrated that p-ezrin expression and binding to PIP2 are required for invadopodia-mediated ECM degradation and invasion and identified NHE1 as the membrane protein that p-ezrin regulates to induce invadopodia formation and activity.
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