The Role of Merlin Phosphorylation on its Tumor Suppressive Activity

Summary

Principal Investigator: Keqiang Ye
Affiliation: Emory University
Country: USA
Abstract: The NF2 tumor suppressor gene encodes an intracellular membrane-associated protein, called merlin or schwannomin, which belongs to the band 4.1 family (ERM proteins) of cytoskeleton-associated proteins that link cell surface glycoproteins to the actin cytoskeleton. Merlin growth suppression is dependent on its ability to form a productive N-term/C-term association. Merlin exists in "open" (inactive form) and "closed" (active growth suppressiveform) conformations, which are regulated by an intramolecular association between the N- and C-termini of the protein. Numerous studies demonstrate that merlin phosphorylation plays an essential role in dictating its conformation and binding activity. Recently, we showed that wild-type merlin, but not patient-derived mutant (L64P), selectively binds PIKE-L and inhibits Phosphoinositol 3-kinase (PI 3- kinase) activity. PIKE (PI 3-Kinase Enhancer) is a brain-specific GTPase that binds to PI 3-kinase and stimulates its lipid kinase activity. This suppression of PI 3-kinase activity results from merlin disrupting the binding of PIKE-L to PI 3-kinase. Induction of merlin substantially diminishes PI 3-kinase/Akt signaling pathway in Schwannoma cells. Phosphorylation and phosphoinositol lipids binding coordinately mediate the activation of ERM proteins. However, whether Akt phosphorylates merlin and phosphoinositol lipids bind to merlin also control merlin activity remains elusive. We hypothesize that merlin is physiologically regulated by a negative feed-back mechanism of PI 3-kinase/Akt cascade. Specifically, we will test whether Akt phosphorylates merlin and modulates its conformation and subcellular localization. In addition, we will determine whether Akt phosphorylation and PI (3,4,5)P3 synergistically mediate merlin's binding activity to the critical downstream effectors, resulting in abolishing merlin's tumor suppressive activity. Identification of signaling pathways mediating merlin phosphorylation and binding activity is essential not only for understanding the physiological functions of merlin, but also for the future development of novel drug treatments for this disease.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Akt phosphorylation of zyxin mediates its interaction with acinus-S and prevents acinus-triggered chromatin condensation
    C B Chan
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 145, Whitehead Building, 615 Michael Street, Atlanta, GA 30322, USA
    Cell Death Differ 14:1688-99. 2007
  2. ncbi Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation
    Xiaoling Tang
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA
    Nat Cell Biol 9:1199-207. 2007
  3. pmc Phosphorylation of merlin regulates its stability and tumor suppressive activity
    Keqiang Ye
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA
    Cell Adh Migr 1:196-8. 2007
  4. pmc Akt phosphorylation of merlin enhances its binding to phosphatidylinositols and inhibits the tumor-suppressive activities of merlin
    Masashi Okada
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Cancer Res 69:4043-51. 2009

Detail Information

Publications4

  1. ncbi Akt phosphorylation of zyxin mediates its interaction with acinus-S and prevents acinus-triggered chromatin condensation
    C B Chan
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Room 145, Whitehead Building, 615 Michael Street, Atlanta, GA 30322, USA
    Cell Death Differ 14:1688-99. 2007
    ..Thus, Akt regulates zyxin/acinus complex formation in the nucleus, contributing to suppression of apoptosis...
  2. ncbi Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation
    Xiaoling Tang
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA
    Nat Cell Biol 9:1199-207. 2007
    ..Furthermore, Akt-mediated phosphorylation leads to merlin degradation by ubiquitination. These studies demonstrate that Akt-mediated merlin phosphorylation regulates the function of merlin in the absence of an inactivating mutation...
  3. pmc Phosphorylation of merlin regulates its stability and tumor suppressive activity
    Keqiang Ye
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA
    Cell Adh Migr 1:196-8. 2007
    ....
  4. pmc Akt phosphorylation of merlin enhances its binding to phosphatidylinositols and inhibits the tumor-suppressive activities of merlin
    Masashi Okada
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Cancer Res 69:4043-51. 2009
    ..Thus, these results suggest that PI3K signaling regulates the tumor-suppressive activity of merlin via both Akt phosphorylation and phosphatidylinositol lipids binding to merlin...