Abstract
The small G-protein Ras is a tightly controlled regulator of cell fate. Prolonged or persistent arrest in the activated GTP-loaded state by mutation of Ras as in lung cancer or in a Ras-GTPase-activating protein as in neurofibromatosis type 1 promotes tumorigenesis. We now show that the tumor-suppressor protein merlin (mutated in neurofibromatosis type 2) also controls Ras activity. Systematic analysis of growth factor signaling located the step of merlin interference to the activation of Ras and Rac. Merlin independently uncouples both Ras and Rac from growth factor signals. In the case of Ras, merlin acts downstream of the receptor tyrosine kinase-growth factor receptor binding protein 2 (Grb2)-SOS complex. However, merlin does not bind either SOS or Ras, but it counteracts the ERM (ezrin, radixin, moesin)-dependent activation of Ras, which correlates with the formation of a complex comprising ERM proteins, Grb2, SOS, Ras, and filamentous actin. Because efficient signaling from Ras requires Rac-p21-activated kinase-dependent phosphorylations of Raf and mitogen-activated protein/extracellular signal-regulated kinase kinase, merlin can also inhibit signal transfer from dominantly active Ras mutants. We propose that the interference of merlin with Ras- and Rac-dependent signal transfer represents part of the tumor-suppressive action of merlin.
Highlights
The autosomal dominant tumor-prone hereditary disorder neurofibromatosis type 2 (NF2) results from mutation of one copy of the nf2 gene
The activities of ERM proteins and merlin are regulated by phosphorylation in an opposite manner: Merlin is activated by dephosphorylation at Ser518 [8, 9], whereas ERM proteins are active upon phosphorylation of a critical threonine residue
As we had shown previously that activated merlin reduced proliferation of cells [9], we examined whether reconstitution in nf2À/À Schwann cells with activated merlin at physiologic abundance would inhibit proliferation
Summary
The autosomal dominant tumor-prone hereditary disorder neurofibromatosis type 2 (NF2) results from mutation of one copy of the nf gene. Mice heterozygous for the nf deletion developed osteomas, aggressive osteosarcomas, and other tumors that had lost the second allele [3], indicating that nf suppresses tumorigenesis in Schwann cells, but more generally, and, possibly, metastatic growth. The nf gene encodes the tumor-suppressor protein merlin. Merlin shares significant NH2-terminal sequence homology with ERM proteins The ERM proteins and merlin seem to act antagonistically on growth: Merlin is inhibitory whereas ERM proteins seem to enhance proliferation [7, 8]. Merlin is activated (and ERM proteins are inactivated) upon cell-tocell or cell-to-matrix contact; this activation step restores contact inhibition of growth to tumor cells [8]
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