Merlin, a "magic" linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival

Our plain-English summary of Merlin, a "magic" linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival, by I. Stamenkovic, Q. Yu (Current Protein & Peptide Science, 2010).

The study

• Authors: I. Stamenkovic, Q. Yu
• Journal: Current Protein & Peptide Science
• Published: 2010;11(6):471-84
• Type of article: Review
• Cited by: 133 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This article was a narrative review, not a new study. The authors summarized published laboratory, animal and human-tumor research on merlin, the protein made by the neurofibromatosis type 2 (NF2) gene. The review did not study asbestos or any other exposure. It noted that NF2 mutations had been found in thyroid cancer, mesotheliomas and melanoma, though less often than in the nervous-system tumors linked to NF2 (schwannomas, meningiomas and ependymomas). The review described merlin's structure, the many proteins it binds, and its reported roles in cell movement, contact inhibition of growth, the Hippo signaling pathway and growth-factor receptors. It cited reports that loss of merlin activated a growth signal called mTORC1 in malignant mesothelioma, meningioma and schwannoma. The authors also described their own earlier work in schwannoma and glioma cells and tumors. In that work merlin blocked the protein CD44 from binding hyaluronan, a substance found around cells, and acted on the Hippo pathway. The authors concluded that merlin is a multifunctional protein linking signals from outside the cell to signaling inside it. They said many of the underlying mechanisms remain to be worked out.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research on the NF2 gene and its protein product, merlin. No search method is described.
• Who was studied: No study population. The review drew on published work in cell lines, Drosophila (fruit flies), mice and human tumors. The reference list has 202 entries.
• Exposure: No asbestos or other exposure was studied. The subject is the biology of the NF2 gene and the merlin protein.
• Main results:
  • Citing earlier work, the review reported that NF2 gene mutations had been found in thyroid cancer, mesotheliomas and melanoma, less frequently than in NF2-associated tumors.
  • The review cited reports that loss or knockdown of merlin led to mTORC1 activation in malignant mesothelioma, meningioma and schwannoma.
  • The authors' earlier work, summarized here, showed that merlin's inhibition of the CD44 and hyaluronan interaction contributed to its tumor-suppressor activity.
  • In the authors' earlier glioma work, re-expressing merlin raised Lats2, inhibited YAP activity and reduced cIAP1/2 expression. They took this to suggest that merlin inhibits glioma growth through the mammalian Hippo pathway.
  • The review proposed a working model in which merlin acts upstream of the mammalian Hippo pathway (merlin, MST1/2, LATS1/2, YAP) and the JNK/p38 pathways.
  • Citing earlier work, the review reported that merlin inhibits schwannoma cell proliferation by promoting breakdown of the platelet-derived growth factor receptor (PDGFR).
• The authors' conclusion: The authors concluded that merlin is a multifunctional protein that integrates and regulates extracellular cues and intracellular signaling pathways controlling cell fate, shape, motility, proliferation and survival.
• Limitations the authors state:
  • The authors stated that the mechanisms by which merlin integrates outside signals into signaling inside the cell remain to be explained.
  • The authors stated that the idea that merlin regulates growth-factor receptor endocytosis through HRS is a hypothesis still to be tested.
  • The authors stated that further studies are needed to establish the possible roles of CD44 in cancer stem cells.

Topics

Medical terms in this study, explained in our Lexicon: Merlin, Mesothelioma, Hippo Signaling Pathway.

Related studies

• Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways — C.W. Menges, E. Sementino, et al. (2012)
• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma — R. Tranchant, L. Quetel, et al. (2018)
• Inhibition of ZL55 cell proliferation by ADP via PKC-dependent signalling pathway — A. Muscella, L.G. Cossa, et al. (2018)
• Novel genes and pathways modulated by syndecan-1: implications for the proliferation and cell-cycle regulation of malignant mesothelioma cells — T. Szatmári, F. Mundt, et al. (2012)
• E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells — T. Kato, T. Sato, et al. (2017)

Browse return to medical research.