Phosphorylation of merlin regulates its stability and tumor suppressive activity.
The neurofibromatosis-2 (NF2) tumor suppressor protein, merlin or schwannomin, inhibits cell proliferation by modulating the growth activities of its binding partners, including the cell surface glycoprotein CD44, membrane-cytoskeleton linker protein ezrin and PIKE (PI 3-kinase enhancer) GTPase, etc. Merlin exerts its growth suppressive activity through a folded conformation that is tightly controlled through phosphorylation by numerous protein kinases including PAK, PKA and Akt. Merlin inhibits PI 3-kinase activity through binding to PIKE-L. Now, we show that merlin is a physiological substrate of Akt, which phosphorylates merlin on both T230 and S315 residues. This phosphorylation abolishes the folded conformation of merlin and inhibits its association with PIKE-L, provoking merlin polyubiquitination and proteasome-mediated degradation. This finding demonstrates a negative feed-back loop from merlin/PIKE-L/PI 3-kinase to Akt in tumors- The proliferation repressive activity of merlin is also partially regulated by S518 phosphorylation- Thus, Akt-mediated merlin T230/S315 phosphorylation, combined with S518 phosphorylation by PAK and PKA, provides new insight into abrogating merlin function in the absence of merlin mutational inactivation.
Ye
Keqiang
K
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA. kye@emory.edu
D000818:Animals; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D017510:Protein Folding; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
C497483:CD44 protein, human; D020690:GTPase-Activating Proteins; D018960:Hyaluronan Receptors; D025581:Neurofibromin 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins