The
neurofibromatosis 2 protein merlin is a classical
tumor suppressor protein. Germline mutations predispose to the development of
schwannomas,
meningiomas and
ependymomas.
Merlin has been implicated in cellular migration and adhesion. This function is reflected in its subcellular localization at the plasma membrane and known interacting partners.
Merlin has been regarded as an exception in not exerting a functional role within the nucleus as other
tumor suppressors do. Here, we show that detection of wild-type
protein in the nucleus is a rare event. However, splicing out of exon 2 leads to unrestricted entry into the nucleus. Skipping of adjacent exon 3 has no comparable effect ruling out an unspecific effect due to misfolding of the 4.1/JEF domain. Exon 2 functions as a cytoplasmic retention factor as it is able to confer sole cytoplasmic localization to a GFP fusion
protein. Nuclear entry of
merlin is thus regulated by alternative splicing within the 4.1/JEF domain and analogous to
band 4.1 protein.
Merlin's ability to enter the nucleus is complemented by a full nuclear-cytoplasmic shuttle
protein with a functional Rev-type nuclear export sequence (NES) within exon 15 that facilitates export via the CRM1/
exportin pathway. Deletion of this NES or treatment with the CRM1-specific inhibitor
leptomycin B leads to overall nuclear accumulation of
merlin isoforms missing exon 2. A cellular function different to the wild-type
protein is implied for naturally occurring splice variants lacking exon 2. A putative effect of
merlin as a transcriptional regulator and identification of nuclear binding partners remains to be elucidated.