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doi: 10.1242/10.1242/jcs.00094

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Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation

Chun-Xiao Sun*, Victoria A. Robb* and David H. Gutmann{ddagger}

Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA



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  		Fig. 1. Structural domains of selected members of the Protein 4.1 superfamily. The defining characteristic of all members is the highly homologous N-terminal FERM domain. The degree of similarity of FERM domains compared with that of the founding member of this superfamily, Protein 4.1R, are as follows: Protein 4.1N, 71%; Protein 4.1G, 74%; Protein 4.1B, 73%; ezrin/moesin/radixin, 24-32%; merlin, 28%; talin, 20%; PTPH, 37%; and NBL4, 40%. Merlin is structurally similar to the ERM proteins and these four proteins comprise the ERM subfamily. Domains shown in the prototypical Protein 4.1 are conserved among all members in the Protein 4.1 subfamily. Talin, PTPH, and NBL4 proteins are shown for comparison. ABD, actin-binding domain; CCR, predicted coiled-coil region; CTD, carboxyl terminal domain; FERM, Protein 4.1-ezrin-radixin-moesin domain; PTP, protein tyrosine phosphatase; SABD, spectrin-actin binding domain; U1, 2, 3, unique regions.

 


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  		Fig. 2. Merlin structure and interactions. (A) Merlin contains three conserved protein-protein interaction domains: a FERM domain in its N-terminus and a C-terminal domain (CTD) separated by a coiled-coil ({alpha}-helical) region. Crystallography showed that the merlin FERM domain contains three subdomains, which exhibits a cloverleaf architecture. Merlin FERM has a unique `Blue Box' (BB, residues 177-183) compared with other ERM proteins. (B) Merlin can adopt two conformations: a `closed' active and `open' inactive form. Merlin can switch from these two conformations as a result of phosphorylation, lipid binding, protein interactions or NF2 mutations. (C) Merlin interacts with several molecules, including NHE-RF, ßII-spectrin, CD44, other ERM proteins, SCHIP-1, HRS, actin and syntenin, which may affect merlin function as a growth suppressor. The proposed domains in merlin that mediate these interactions are depicted.

 


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  		Fig. 3. Alignment of Protein 4.1B and DAL-1. Protein 4.1B contains unique sequences not present in DAL-1. DAL-1 is represented by residues M110 and S542, with deletions in the N- and C-termini and internal deletions within the U2 and SAB domains. Brackets denote internal sequences absent in DAL-1.

 


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  		Fig. 4. Proposed model for merlin tumor suppressor function. In the growth permissive state (growth factor receptor ligand binding), ERM proteins and merlin are phosphorylated by a cascade of kinases stimulated by Rho and Rac1 activation. Activated ERM proteins associate with CD44 cytoplasmic tail and promote cell growth, survival and motility. `Open' phosphorylated merlin resides in an inactive conformation and may associate with ERM proteins. In the growth arrest state (high molecular weight hyaluronic acid binding to CD44 receptor), this protein kinase cascade is not activated and ERM proteins are not phosphorylated. Merlin, in the hypophosphorylated form, is `closed' and active. `Active' merlin interacts with CD44 to facilitate inhibition of cell growth and motility. ERM proteins in the `closed' conformation would be predicted to dissociate from the CD44 complex. GFR, growth factor receptor; HA, hyaluronic acid.

 

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