Merlin is encoded by the
neurofibromatosis type 2 (NF2) gene and is a member of the
Band 4.1 protein family. This
protein acts as a linker that connects
cell surface proteins to the actin cytoskeleton. Defects caused by mutations of the NF2 gene give rise to NF2 disease, which is generally characterized by the formation of bilateral
vestibular schwannomas and, to a lesser extent,
meningiomas and
ependymomas. In addition to these
tumor types, NF2 is mutated and/or
merlin expression is reduced or lost in numerous non-NF2 associated
tumors, including
melanoma. However, the role of
merlin in human
melanoma growth and the mechanism underlying its effect are currently unknown. In the present study, we show that
merlin knockdown enhances
melanoma cell proliferation, migration, and invasion in vitro and that decreased
merlin expression promotes subcutaneous
melanoma growth in immunocompromised mice. Concordantly, we find that increased expression of
merlin in a metastatic
melanoma cell line reduced their in vitro migration and proliferation, and diminished their ability to grow in an anchorage independent manner. Increased
merlin expression also inhibits in vivo growth of these
melanoma cells. Lastly, we demonstrate that higher
merlin levels in human
melanoma cells promote the H(2)O(2)-induced activation of MST1/2 Ser/Thr
kinases, which are known
tumor suppressors in the Hippo signaling pathway. Taken together, these results provide for the first time evidence that
merlin negatively regulates human
melanoma growth, and that loss of
merlin, or impaired
merlin function, results in an opposite effect. In addition, we show that increased
merlin expression leads to enhanced activation of the MTS1/2
kinases, implying the potential roles of MST1/2 in mediating the anti-
melanoma effects of
merlin.