Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane - PubMed (original) (raw)

Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane

B Deguen et al. Hum Mol Genet. 1998 Feb.

Abstract

Although schwannomin, the product of the neurofibromatosis type 2 gene, shares homology with three cytoskeleton-to-membrane protein linkers defining the ERM family, the mechanism by which it exerts a tumor suppressive activity remains elusive. Based on the knowledge of naturally occurring mutations, a functional study of schwannomin was initiated. Constructs encoding the two wild-type isoforms and nine mutant forms were transfected into HeLa cells. Transiently expressed wild-type isoforms were both observed underneath the plasma membrane. At this location they were detergent insoluble and redistributed by a cytochalasin D treatment, suggesting interaction with actin-based cytoskeletal structures. Proteins with single amino acid substitutions at positions 219 and 220 demonstrated identical properties. Three different truncated schwannomins, that are prototypic for most naturally occurring NF2 mutations, were affected neither in their location nor in their cytochalasin D sensitivity. However, they were revealed to be detergent soluble, indicating a relaxed interaction with the actin-based structures. An increased solubility was also observed for a mutant with a single amino acid substitution at position 360 in the C-terminal half of the protein. Mutant proteins with either a single amino acid deletion at position 118 or an 83 amino acid deletion within the N-terminal domain had lost the submembraneous localization and tended to accumulate in perinuclear patches that were unaffected by cytochalasin D treatment. A similar behavior was observed when the N-terminal domain was entirely deleted. Taken together these observations suggest that the N-terminal domain is the main determinant that localizes the protein at the membrane where it interacts weakly with actin-based cytoskeletal structures. The C-terminal domain potentiates this interaction. With rare exceptions, most naturally occurring mutant schwannomins that have lost their tumor suppressive activity are impaired in an interaction involving actin-based structures and are no longer firmly maintained at the membrane.

PubMed Disclaimer

Cited by

Detection of spontaneous schwannomas by MRI in a transgenic murine model of neurofibromatosis type 2.
Messerli SM, Tang Y, Giovannini M, Bronson R, Weissleder R, Breakefield XO. Messerli SM, et al. Neoplasia. 2002 Nov-Dec;4(6):501-9. doi: 10.1038/sj.neo.7900265. Neoplasia. 2002. PMID: 12407444 Free PMC article.
Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2.
Chinthalapudi K, Mandati V, Zheng J, Sharff AJ, Bricogne G, Griffin PR, Kissil J, Izard T. Chinthalapudi K, et al. Nat Commun. 2018 Apr 6;9(1):1338. doi: 10.1038/s41467-018-03648-4. Nat Commun. 2018. PMID: 29626191 Free PMC article.
Imaging and therapy of experimental schwannomas using HSV amplicon vector-encoding apoptotic protein under Schwann cell promoter.
Prabhakar S, Brenner GJ, Sung B, Messerli SM, Mao J, Sena-Esteves M, Stemmer-Rachamimov A, Tannous B, Breakefield XO. Prabhakar S, et al. Cancer Gene Ther. 2010 Apr;17(4):266-74. doi: 10.1038/cgt.2009.71. Epub 2009 Oct 16. Cancer Gene Ther. 2010. PMID: 19834516 Free PMC article.
Pathological adhesion of primary human schwannoma cells is dependent on altered expression of integrins.
Utermark T, Kaempchen K, Hanemann CO. Utermark T, et al. Brain Pathol. 2003 Jul;13(3):352-63. doi: 10.1111/j.1750-3639.2003.tb00034.x. Brain Pathol. 2003. PMID: 12946024 Free PMC article.

Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane - PubMed (original) (raw)