Akt phosphorylation of merlin enhances its binding to phosphatidylinositols and inhibits the tumor-suppressive activities of merlin.
The NF2 tumor suppressor gene encodes an intracellular membrane-associated protein, called merlin, which belongs to the band 4.1 family of cytoskeleton-associated proteins that link cell surface glycoproteins to the actin cytoskeleton. Merlin suppresses phosphatidylinositol 3-kinase (PI3K)/Akt signaling by directly binding and inhibiting the stimulatory activity of PIKE-L on PI3K. Akt feeds back and phosphorylates merlin and provokes its polyubiquitination and degradation. Here, we show that Akt phosphorylation and PI(3,4,5)P(3) binding mediate the tumor-suppressive activity of merlin. The extreme NH(2) terminus of merlin directly interacts with phosphatidylinositols, for which the unfolded conformation is required. Moreover, Akt phosphorylation enhances merlin binding affinity to phosphatidylinositols and inhibits its proapoptotic actions. Furthermore, Akt phosphorylation and phosphatidylinositols increase merlin binding to CD44. Epidermal growth factor treatment and Akt phosphorylation provoke merlin to aggregate in the ruffled plasma membrane and promote cell migration. Thus, these results suggest that PI3K signaling regulates the tumor-suppressive activity of merlin via both Akt phosphorylation and phosphatidylinositol lipids binding to merlin.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Masashi
M
Okada
Yanru
Y
Wang
Sung-Wuk
SW
Jang
Xiaoling
X
Tang
Luca M
LM
Neri
Keqiang
K
Ye
D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008968:Molecular Conformation; D009442:Neurilemmoma / Q000378:metabolism; D025581:Neurofibromin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008081:Liposomes; D025581:Neurofibromin 2; D010716:Phosphatidylinositols; D051057:Proto-Oncogene Proteins c-akt