Home > A. Molecular pathology > NF2
NF2
Tuesday 25 November 2003
Homologies
The NF2 gene product, merlin, exhibits homology with the ezrin-radixin-moesin family of membrane-cytoskeleton-linking proteins (EMR proteins): VIL2 (ezrin), MSN (moesin), RDX (radixin).
The product of the NF-2 gene, called merlin, shows a great deal of homology with the red cell membrane cytoskeletal protein 4.1.
Merlin is related to the ERM proteins (ezrin (VIL2), radixin (RDX), and moesin (MSN)) family of membrane cytoskeleton-associated proteins.
Function
Merlin binds, on one hand, to actin and, on the other hand, to CD44, a transmembrane protein that is involved in cell-matrix interactions.
Merlin is an Ezrin-Radixin-Moesin protein and localizes underneath the plasma membrane at cell-cell junctions and other actin-rich sites.
Merlin mediates contact inhibition of proliferation by blocking recruitment of Rac to the plasma membrane.
In mitogen-stimulated cells, p21-activated kinase phosphorylates Ser518 in the C-terminus of Merlin, inactivating the growth suppressive function of the protein.
The myosin phosphatase MYPT1-PP1delta, has been identified as a direct activator of Merlin and its inhibition has been linked to malignant transformation.
Studies in the fruit fly Drosophila melanogaster have revealed that Merlin functions together with the band 4.1 protein Expanded to block the endocytosis of many signaling receptors, causing their accumulation at the plasma membrane, and to inactivate the Hippo signaling pathway.
Pathology
Germ line mutations in the NF-2 gene predispose to the development of neurofibromatosis type 2. Patients with NF-2 deficiency develop benign bilateral schwannomas of the acoustic nerve. In addition, somatic mutations affecting both alleles of NF2 have also been found in sporadic meningiomas and ependymomas.
Although the mechanism by which NF2 deficiency leads to carcinogenesis is not known, cells lacking merlin are not capable of establishing stable cell-to-cell junctions and are insensitive to normal growth arrest signals generated by cell-to-cell contact.
somatic mutations in schwannomas
somatic mutations in sclerosing perineurioma
somatic mutations in intracranial meningiomas
germline mutations in neurofibromatosis type 2
- People with constitutional NF2 missense mutations, splice-site mutations, large deletions, or somatic mosaicism had significantly fewer tumors than did people with constitutional nonsense or frameshift NF2 mutations. (15190457)
- Significant intrafamilial correlations for intracranial meningiomas and spinal tumors, after adjustment for the type of constitutional NF2 mutation. (15190457)
See also
EMR proteins (VIL2, MSN, RDX)
References
Okada T, You L, Giancotti FG. Shedding light on Merlin’s wizardry. Trends Cell Biol. 2007 Apr 16; PMID: 17442573
Ramesh V. Merlin and the ERM proteins in Schwann cells, neurons and growth cones. Nat Rev Neurosci. 2004 Jun;5(6):462-70. PMID: 15152196
McClatchey AI. Merlin and ERM proteins: unappreciated roles in cancer development? Nat Rev Cancer. 2003 Nov;3(11):877-83. PMID: 14668818
Xiao GH, Chernoff J, Testa JR. NF2: The wizardry of merlin. Genes Chromosomes Cancer. 2003 Dec;38(4):389-99. PMID: 14566860
Sherman LS, Gutmann DH. Merlin: hanging tumor suppression on the Rac. Trends Cell Biol. 2001 Nov;11(11):442-4. PMID: 11684412
