Shaw, R. are believed to switch between a closed conformation, which is inactive, and an open conformation, which mediates the linkage of certain cell adhesion proteins to the actin cytoskeleton. In contrast to classical ERM proteins, merlin does not contain a standard actin-binding motif. In addition, although merlin also switches between an open and a closed conformation, it Mouse monoclonal to SRA is the closed form that suppresses tumorigenesis and is thereby considered active (25, 37, 57). The serine/threonine kinase p21-activated kinase (PAK) inactivates merlin by phosphorylating its C-terminal tail at Ser 518 and thereby disrupting the intramolecular interaction between the FERM domain and the C-terminal tail, which maintains the protein in the closed conformation (21, 56, 67). Conversely, the protein UNC0631 phosphatase MYPT1-PP1 is thought to promote merlin-mediated growth inhibition by reversing the phosphorylation of Ser 518 (19). Distinct adhesion-dependent stimuli converge on merlin to regulate cell proliferation. Cadherin-dependent cell-to-cell adhesion and CD44 engagement by hyaluronic acid activate MYPT1-PP1 and inhibit PAK, causing an accumulation of dephosphorylated, closed-conformation merlin (19, 33, 38, 55). In contrast, integrin-dependent adhesion to the extracellular matrix activates PAK, causing inactivation of merlin and thereby presumably removing a block to cell cycle progression (38). These results suggest that merlin functions as a phosphorylation-dependent switch downstream of cell adhesion receptors. Although significant progress has been made toward elucidating the UNC0631 mechanisms that act upon merlin to regulate growth suppression, the biochemical function of merlin and the critical effector pathways through which it suppresses tumorigenesis have remained elusive. Several studies have provided evidence that the closed form of merlin inhibits Rac signaling (22, 34, 38, 56). In this model, PAK-mediated inactivation of merlin would enhance Rac signaling, either by removing a block to the recruitment of Rac to the plasma membrane (38) or by alleviating direct inhibition of PAK (22). Indeed, NF2-deficient schwannoma cells display large lamellipodia and membrane ruffles, which are distinctive of activated Rac signaling (44). Other studies have documented effects of merlin on the Ras-extracellular signal-regulated kinase (ERK) pathway (19, 34), the phosphatidylinositol 3-kinase (PI-3K)-AKT pathway (49), and focal adhesion kinase signaling (46). Recently, it has been shown that merlin binds to the cytoplasmic tails of receptor tyrosine kinases (RTKs) in contact-inhibited cells and that, although merlin decreases the rate at which the RTKs are internalized, it hinders their abilities to initiate signaling (7). In apparent contrast, studies of the fruit fly have indicated that merlin does not decrease, but rather increases, the rate of internalization of RTKs and other cell surface receptors, thus reducing their signaling activities (27). Finally, the UNC0631 results of genetic epistasis experiments with the same model indicate that merlin cooperates with the related ERM protein Expanded to activate the Hippo tumor suppressor pathway, which impinges within the transcriptional activator Yorkie (5, 16, 43). Although it is possible and, indeed, likely that loss of merlin activates several mitogenic pathways, it remains unclear whether any of the recognized pathways are critical for NF2-dependent tumorigenesis. Integrins bind to extracellular matrix parts and cooperate with RTKs and additional cytokine receptors to regulate cell survival and cell cycle progression (8, 13, 63). Most of the evidence to date suggests that the integrins control cell fate by regulating transcription. However, increasing evidence suggests that integrin-mediated adhesion also influences mRNA translation. Maeshima and colleagues have shown that tumstatin, an antiangiogenic fragment of collagen type IV, binds to the v3 integrin and suppresses mTORC1 signaling and cap-dependent translation in endothelial cells (26). Furthermore, it has been demonstrated the engagement of IIb3 by fibrinogen induces translation of the mRNA encoding UNC0631 Bcl-3 in triggered platelets through a.