Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2

Abstract

Neurofibromatosis type 2 (NF2) is a tumor-forming disease of the nervous system caused by deletion or by loss-of-function mutations in NF2, encoding the tumor suppressing protein neurofibromin 2 (also known as schwannomin or merlin). Neurofibromin 2 is a member of the ezrin, radixin, moesin (ERM) family of proteins regulating the cytoskeleton and cell signaling. The correlation of the tumor-suppressive function and conformation (open or closed) of neurofibromin 2 has been subject to much speculation, often based on extrapolation from other ERM proteins, and controversy. Here we show that lipid binding results in the open conformation of neurofibromin 2 and that lipid binding is necessary for inhibiting cell proliferation. Collectively, our results provide a mechanism in which the open conformation is unambiguously correlated with lipid binding and localization to the membrane, which are critical for the tumor-suppressive function of neurofibromin 2, thus finally reconciling the long-standing conformation and function debate.

Phosphorylation of Merlin by Aurora A kinase appears necessary for mitotic progression

“…T581 phosphorylation abolishes Merlin C-terminal interaction with Ezrin FERM domain and promotes Merlin binding to α-tubulin. It also decreases Merlin head to tail interaction ( Figure 4F) and is more likely to participate in Merlin open conformation than S518 phosphorylation, in coherence with results reported recently (51,52) Interestingly this phosphorylation confers to isoform 1 interaction properties that are similar to those of isoform 2. Indeed, isoform 2 doesn't interact with Ezrin Ferm domain via its C-terminal end and binds more efficiently to α-tubulin than isoform 1 via its FERM domain.…”

The interaction of talin with the cell membrane is essential for integrin activation and focal adhesion formation

“…We determined lipid binding via a lipid cosedimentation assay ( Fig. 2A), which we used previously to detect micromolar lipid binding (43). The mutant showed approximately 12-fold less binding (as assessed using ImageJ) to the lipid vesicles compared with the wild-type talin.…”

Phosphatidic Acid Signals via the Hippo Pathway

“…PA binding did not affect NF2 membrane recruitment but, interestingly, was shown to bind to the FERM domain within NF2, a domain previously shown to associate with phosphorylated phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (Mani et al, 2011). PIP 2 has been reported to induce NF2 recruitment to the plasma membrane and promotes an active structural conformation that leads to stronger (approximately 10-fold) binding to LATS1 (Chinthalapudi et al, 2018;Mani et al, 2011). Therefore, it appears that different phospholipids have distinct and possibly competing functions on NF2 to direct Hippo pathway signaling.…”