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lüll Phosphorylation of merlin regulates its stability and tumor suppressive activity Ye KCell Adh Migr 2007[Oct]; 1 (4): 196-8The 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.|*Cell Proliferation[MESH]|*Protein Folding[MESH]|Animals[MESH]|Cyclic AMP-Dependent Protein Kinases/genetics/metabolism[MESH]|GTP-Binding Proteins/genetics/metabolism[MESH]|GTPase-Activating Proteins/genetics/metabolism[MESH]|Humans[MESH]|Hyaluronan Receptors/genetics/metabolism[MESH]|Neurofibromin 2/genetics/*metabolism[MESH]|Phosphatidylinositol 3-Kinases/genetics/metabolism[MESH]|Phosphorylation/genetics[MESH]|Protein Stability[MESH]|Proto-Oncogene Proteins c-akt/genetics/metabolism[MESH]|Ubiquitination/genetics[MESH]|p21-Activated Kinases/genetics/metabolism[MESH] |