Abstract
The neurofibromatosis type 2 tumor suppressor gene, NF2, is mutated in the germ line of NF2 patients and predisposes affected individuals to intracranial and spinal tumors. Moreover, somatic mutations of NF2 can occur in the sporadic counterparts of these neurological tumor types as well as in certain neoplasms of non-neuroectodermal origin, such as malignant mesothelioma and melanoma. NF2 encodes a 595-amino acid protein, merlin, which exhibits significant homology to the ezrin-radixin-moesin family of proteins. However, the mechanism by which merlin exerts its tumor suppressor activity is not well understood. In this investigation, we show that merlin is phosphorylated in response to expression of activated Rac and activated Cdc42 in mammalian cells. Furthermore, we demonstrate that merlin phosphorylation is mediated by p21-activated kinase (Pak), a common downstream target of both Rac and Cdc42. Both in vivo and in vitro kinase assays demonstrated that Pak can directly phosphorylate merlin at serine 518, a site that affects merlin activity and localization. These biochemical investigations provide insights into the regulation of merlin function and establish a framework for elucidating tumorigenic mechanisms involved in neoplasms associated with merlin inactivation.
Highlights
From the ‡Human Genetics Program and §Tumor Cell Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111
We demonstrate that merlin phosphorylation is mediated by p21-activated kinase (Pak), a common downstream target of both Rac and Cdc42
Our investigations have determined that merlin is phosphorylated in response to constitutively active Rac1 and, to a lesser extent, Cdc42, and this phosphorylation is mediated by the Rac/Cdc42 effector, p21-activated kinase (Pak)
Summary
The mechanism by which merlin exerts its tumor suppressor activity is not well understood In this investigation, we show that merlin is phosphorylated in response to expression of activated Rac and activated Cdc in mammalian cells. We demonstrate that merlin phosphorylation is mediated by p21-activated kinase (Pak), a common downstream target of both Rac and Cdc. Both in vivo and in vitro kinase assays demonstrated that Pak can directly phosphorylate merlin at serine 518, a site that affects merlin activity and localization These biochemical investigations provide insights into the regulation of merlin function and establish a framework for elucidating tumorigenic mechanisms involved in neoplasms associated with merlin inactivation. Our investigations have determined that merlin is phosphorylated in response to constitutively active Rac and, to a lesser extent, Cdc, and this phosphorylation is mediated by the Rac/Cdc effector, p21-activated kinase (Pak)
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