Human Molecular Genetics, Vol 7, 217-226, Copyright © 1998 by Oxford University Press
B Deguen, P Merel, L Goutebroze, M Giovannini, H Reggio, M Arpin and G Thomas
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.
ARTICLES
Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane
Laboratoire de Genetique des Tumeurs, INSERM U434, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
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