Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology

Abstract

Neurofibromatosis type 2 is an autosomal dominant disorder characterized by tumors, predominantly schwannomas, in the nervous system. It is caused by mutations in the gene NF2, encoding the growth regulator schwannomin (also known as merlin). Mutations occur throughout the 17-exon gene, with most resulting in protein truncation and undetectable amounts of schwannomin protein. Pathogenic mutations that result in production of defective schwannomin include in-frame deletions of exon 2 and three independent missense mutations within this same exon. Mice with conditional deletion of exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. Here we report that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta 1 integrin and erbB2. It defines a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2.

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

“…Alternatively, merlin could spatially restrict growth factor receptors and adhesion molecules accumulation within the plasma membrane. In SCs, it has been reported that merlin interacts with ErbB2 hence controlling its subcellular localization (Fernandez-Valle et al, 2002). Therefore, loss of merlin expression could allow for a broader distribution of membrane-associated proteins.…”

Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves

“…This could be a consequence of the ability of schwannomin to inhibit Pak1-mediated recruitment of Rac to the plasma membrane and matrix adhesions (Shaw et al, 2001;Morrison et al, 2007;Okada et al, 2007). Schwannomin may also have a regulatory role through its interactions with ErbB2 (Fernandez-Valle et al, 2002), a receptor for the axonal factor neuregulin-1, critical for the control of myelin thickness (Garratt et al, 2000;Michailov et al, 2004). Additional signs of altered axon-Schwann cell interactions included the frequent protrusions originating from one cell type into the other, including the formation of axonSchwann cell networks.…”

“…Schwannomin-like immunoreactivity has been reported in paranodal regions and SchmidtLanterman incisures (SLIs) (Scherer and Gutmann, 1996), which are cytoplasmic channels interrupting the compact myelin. In neurons, schwannomin can associate with the cytoplasmic tail of the paranodal protein paranodin/Caspr (Denisenko-Nehrbass et al, 2003), whereas in Schwann cells, it is localized to the plasma membrane through a paxillin-mediated interaction with ␤1-integrin (Obremski et al, 1998;Fernandez-Valle et al, 2002).…”

Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2

“…Merlin interacts with F-actin through actin binding sites within the FERM domain (Xu and Gutmann, 1998;Brault et al, 2001;James et al, 2001). In addition to actin, several other merlin interacting proteins have been identified, which include b-fodrin/bII-spectrin (Scoles et al, 1998;Neill and Crompton, 2001), SCHIP-1 (Goutebroze et al, 2000), NHE-RF (Murthy et al, 1998), b1-integrin (Obremski et al, 1998), CD44 (Sainio et al, 1997;Morrison et al, 2001), HRS (Scoles et al, 2000), RhoGDI (Maeda et al, 1999), syntenin (Jannatipour et al, 2001), paxillin (Fernandez-Valle et al, 2002) and RIb subunit of the cAMP-protein kinase A (Gronholm et al, 2003). Among these proteins, NHE-RF, CD44 and RhoGDI have been independently identified as ERM binding partners (Tsukita et al, 1994;Reczek et al, 1997;Takahashi et al, 1997), while HRS and syntenin appear to be specific for merlin.…”