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Phosphorylation of merlin at <scene name='Sandbox_Reserved_705/Resi/1'>Thr-230</scene> and <scene name='Sandbox_Reserved_705/Rez/1'>Ser-315</scene> target the protein for ubiquitination,degradation <ref>PMID:17891137</ref>.This is a mechanism that lowers merlin expression in breast cancer<ref>PMID:21965655</ref>.
Phosphorylation of merlin at <scene name='Sandbox_Reserved_705/Resi/1'>Thr-230</scene> and <scene name='Sandbox_Reserved_705/Rez/1'>Ser-315</scene> target the protein for ubiquitination,degradation <ref>PMID:17891137</ref>.This is a mechanism that lowers merlin expression in breast cancer<ref>PMID:21965655</ref>.
However there exist many protein that regulates merlin expression. They may be a useful therapetic target.Therefore scientist need to further inverstigate to determine the pathways that involve the merlin protein.
However there exist many protein that regulates merlin expression. They may be a useful therapetic target.Therefore scientist need to further inverstigate to determine the pathways that involve the merlin protein.
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'''Je peux modifier la page'''

Revision as of 00:06, 24 December 2012


Human Merlin FERM Domain

Human Merlin FERM Domain 3u8Z

Drag the structure with the mouse to rotate

Contents

Introduction

The merlin-1 protein is encoded by the Neurofibromatosis-2(Nf2) gene. Neurofibromatosis type 2 is an inheritable autosomal dominant disorder. Patients develop tumors of the nervous system : meningiomas, schwannomas, neurofibromas.[1] Mutations in the Nf2 gene lead to tumor proliferation as well in humans as in mice. Therefore Merlin-1 is a tumor suppressor protein. To know more about the type of Nf2 mutations and the related deseases you can follow the link that leads you to the Portal to Swiss-Prot diseases and variants the Portal to Swiss-Prot diseases and variants

ERM Proteins

The merlin-1 protein belongs to the band 4.1 superfamily of membrane-cytoskeletal linkers [2]. Within this superfamily merlin-1 is closer to ezrin,radixin and moesin (the ERM proteins). ERM proteins link Adhrens Junctions to the actin cytoskeleton,and are able to remodel Adherens Junctions during epithelial morphogenesis. They also maintain the organization of apical surfaces on the plasma membrane [3].

Structural organization

All these proteins have an about 300-residue globular plasma membrane-associated FERM domain(four-point-one ezrin, radixin, moesin).This FERM domain is a highly conserved domain. This domain is divided into three subdomains (F1, F2, and F3). ERM proteins are composed of a FERM domain followed by a long region with a high α-helical propensity and terminating in a C-terminal domain[4].

Domain organization of ERM
Domain organization of ERM[4]

Regulation of the activity

The acitivity of ERM proteins is caused by the association of different regions within the protein. The C-terminal tail domain contains an F-actin binding site in the last 30 residues. This domain interacts with the FERM domain as an extended, meandering polypeptide beginning with a β-strand associated with β5 in F3 followed by four helices. The two first helices bind l and the two second lobe F3. The FERM-tail complex represents an inactive form of the protein in which membrane protein and active binding sites are masked.[5] The ERM proteins are regulated by changing from a closed conformation to an open, active state. This is due to severing of intramolecular head–tail interactions,and also of interactions between their FERM domain and α-helical domains[6].Conformational changes modify the intramolecular contacts, allowing these proteins to bind to their partners. The protein is in an active state.The FERM domain has a fundamental role because it allows ERM proteins to interact with integral proteins of the plasma membrane[7].

Inactive ERM protein
Inactive ERM protein
Active ERM protein
Active ERM protein











Regulators of the activity

Phosphorylation of a C-terminal threonine by Rho kinase and binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and protein partners, is necessary for full activation of ERM proteins [8]. They disrupt the head to tail interactions. The phosphorylations and/binding(s) determine the cellular localization and the cellular function of each specific ERM protein[9].



Merlin shares certain properties with the ERM family : they both have a subcellular localization to cortical actin structures and they both bind to adhesion receptors.These receptors are CD44 [10] and E-cadherin [11]. However Merlin-1 has some properties not shared with ERM proteins.


Specificity of merlin FERM domain

PDB ID 3u8z

Drag the structure with the mouse to rotate
3u8z, resolution 2.64Å ()
Gene: NF2, SCH (Homo sapiens)


Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml


As showed in the default scene, the structure 3U8Z has in total 4 chains. These are represented by 1 sequence-unique entity. The chains A,B and C possess 9 Alpha Helices and 15  Beta Strands  and the chain D has only 9 Alpha Helicesand 14  Beta Strands . You can visualize their .

Structural differences

The overall architecture of merlin is similar to that of ERM proteins. Indeed they have almost the same organization : a FERM domain,a central α-helical rod, but lack a C-terminal actin-binding site[6]. The closed complex of the Merlin proteins corresponds to the tumor suppressor-active form. As the N-terminus FERM domain and C-terminus are maintained associated, Merlin is in a closed conformation and is able to promote nuclear translocation and inhibt growth[12]. More precisly,binding of the tail provokes dimerization and unfurling of the F2 motif of the FERM domain.The “closed” complex of merlin-1 is in fact an “open” dimer [4].

Merlin regulation

and Ser-518 phosphorylation by protein kinase A (PKA) and/or p21-activated kinase(PAK) trigger the "closed" complex [13]. Phosphorylation by PAK and PKA at Ser 518 renders the protein inactive, it reduces the inhibition of cell growth.

Merlin possess a serine 10 that can be phosphorylated by Akt. This phosphorylation directs merlin for proteasome-mediated degradation.[14].

Tumor suppressive function

The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is often involved in tumor proliferation.Indeed overexpression of Akt is often associated with tumor development[15]. Merlin plays a role in controlling the PI3K/Akt pathway by inhibiting Akt signaling [16].


CD44 is a cell-surface receptor for hyaluronan (HA a ligand). When HA binds to CD44 the complex promotes tumorigenesis it means it promotes tumor invasion and metastasis.[17] .

Applications

Nowadays, late stage melanoma is resistant to any treatment.To achieve better therapies for patients, we need to understand better the signaling pathways of melanoma progression. Merlin is a target that is seriously considered. Its levels and activity can be modulated through post-translational modifications[18]. Phosphorylation at Ser518 of merlin inactivates its growth inhibitive activity. As we explained this phosphorylation can be achieved by cyclic AMP-dependent protein PKA and PAK1. Phosphorylation of merlin at and target the protein for ubiquitination,degradation [19].This is a mechanism that lowers merlin expression in breast cancer[20]. However there exist many protein that regulates merlin expression. They may be a useful therapetic target.Therefore scientist need to further inverstigate to determine the pathways that involve the merlin protein.

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References

  1. ↑ Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med. 1988 Mar 17;318(11):684-8. PMID:3125435 doi:http://dx.doi.org/10.1056/NEJM198803173181106
  2. ↑ Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, et al.. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993 Nov 19;75(4):826. PMID:8242753
  3. ↑ Brault E, Gautreau A, Lamarine M, Callebaut I, Thomas G, Goutebroze L. Normal membrane localization and actin association of the NF2 tumor suppressor protein are dependent on folding of its N-terminal domain. J Cell Sci. 2001 May;114(Pt 10):1901-12. PMID:11329377
  4. ↑ 4.0 4.1 4.2 Fehon RG, McClatchey AI, Bretscher A. Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol. 2010 Apr;11(4):276-87. doi: 10.1038/nrm2866. PMID:20308985 doi:10.1038/nrm2866
  5. ↑ Li Q, Nance MR, Kulikauskas R, Nyberg K, Fehon R, Karplus PA, Bretscher A, Tesmer JJ. Self-masking in an intact ERM-merlin protein: an active role for the central alpha-helical domain. J Mol Biol. 2007 Feb 2;365(5):1446-59. Epub 2006 Oct 26. PMID:17134719 doi:10.1016/j.jmb.2006.10.075
  6. ↑ 6.0 6.1 Yogesha SD, Sharff AJ, Giovannini M, Bricogne G, Izard T. Unfurling of the band 4.1, ezrin, radixin, moesin (FERM) domain of the merlin tumor suppressor. Protein Sci. 2011 Oct 19. doi: 10.1002/pro.751. PMID:22012890 doi:10.1002/pro.751
  7. ↑ Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99. PMID:12154370 doi:10.1038/nrm882
  8. ↑ Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D, Arpin M. Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol. 2004 Mar 1;164(5):653-9. PMID:14993232 doi:10.1083/jcb.200307032
  9. ↑ Mani T, Hennigan RF, Foster LA, Conrady DG, Herr AB, Ip W. FERM domain phosphoinositide binding targets merlin to the membrane and is essential for its growth-suppressive function. Mol Cell Biol. 2011 May;31(10):1983-96. doi: 10.1128/MCB.00609-10. Epub 2011 Mar , 14. PMID:21402777 doi:10.1128/MCB.00609-10
  10. ↑ Vaheri A, Carpen O, Heiska L, Helander TS, Jaaskelainen J, Majander-Nordenswan P, Sainio M, Timonen T, Turunen O. The ezrin protein family: membrane-cytoskeleton interactions and disease associations. Curr Opin Cell Biol. 1997 Oct;9(5):659-66. PMID:9330869
  11. ↑ Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 2003 May 1;17(9):1090-100. Epub 2003 Apr 14. PMID:12695331 doi:10.1101/gad.1054603
  12. ↑ Li W, Cooper J, Karajannis MA, Giancotti FG. Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus. EMBO Rep. 2012 Mar;13(3):204-15. PMID:22482125
  13. ↑ Laulajainen M, Muranen T, Carpen O, Gronholm M. Protein kinase A-mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects the actin cytoskeleton. Oncogene. 2008 May 22;27(23):3233-43. Epub 2007 Dec 10. PMID:18071304 doi:10.1038/sj.onc.1210988
  14. ↑ Laulajainen M, Muranen T, Nyman TA, Carpen O, Gronholm M. Multistep phosphorylation by oncogenic kinases enhances the degradation of the NF2 tumor suppressor merlin. Neoplasia. 2011 Jul;13(7):643-52. PMID:21750658
  15. ↑ Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002 Jul;2(7):489-501. PMID:12094235 doi:10.1038/nrc839
  16. ↑ Rong R, Tang X, Gutmann DH, Ye K. Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18200-5. Epub 2004 Dec 14. PMID:15598747 doi:0405971102
  17. ↑ Morrison H, Sherman LS, Legg J, Banine F, Isacke C, Haipek CA, Gutmann DH, Ponta H, Herrlich P. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev. 2001 Apr 15;15(8):968-80. PMID:11316791 doi:10.1101/gad.189601
  18. ↑ Murray LB, Lau YK, Yu Q. Merlin is a negative regulator of human melanoma growth. PLoS One. 2012;7(8):e43295. doi: 10.1371/journal.pone.0043295. Epub 2012 Aug 17. PMID:22912849 doi:10.1371/journal.pone.0043295
  19. ↑ Tang X, Jang SW, Wang X, Liu Z, Bahr SM, Sun SY, Brat D, Gutmann DH, Ye K. Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. Nat Cell Biol. 2007 Oct;9(10):1199-207. Epub 2007 Sep 23. PMID:17891137 doi:10.1038/ncb1641
  20. ↑ Morrow KA, Das S, Metge BJ, Ye K, Mulekar MS, Tucker JA, Samant RS, Shevde LA. Loss of tumor suppressor Merlin in advanced breast cancer is due to post-translational regulation. J Biol Chem. 2011 Nov 18;286(46):40376-85. doi: 10.1074/jbc.M111.250035. Epub, 2011 Sep 30. PMID:21965655 doi:10.1074/jbc.M111.250035

External Resources

  • Li Q, Nance MR, Kulikauskas R, Nyberg K, Fehon R, Karplus PA, Bretscher A, Tesmer JJ. Self-masking in an intact ERM-merlin protein: an active role for the central alpha-helical domain. J Mol Biol. 2007 Feb 2;365(5):1446-59. Epub 2006 Oct 26. PMID:17134719 doi:10.1016/j.jmb.2006.10.075
  • Hennigan RF, Moon CA, Parysek LM, Monk KR, Morfini G, Berth S, Brady S, Ratner N. The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38(SAPK) pathway. Oncogene. 2012 Apr 23. doi: 10.1038/onc.2012.135. PMID:22525268 doi:10.1038/onc.2012.135
  • Sun CX, Robb VA, Gutmann DH. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. J Cell Sci. 2002 Nov 1;115(Pt 21):3991-4000. PMID:12356905
  • Johnson KC, Kissil JL, Fry JL, Jacks T. Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene. Oncogene. 2002 Sep 5;21(39):5990-7. PMID:12203111 doi:10.1038/sj.onc.1205693
  • Li Q, Nance MR, Kulikauskas R, Nyberg K, Fehon R, Karplus PA, Bretscher A, Tesmer JJ. Self-masking in an intact ERM-merlin protein: an active role for the central alpha-helical domain. J Mol Biol. 2007 Feb 2;365(5):1446-59. Epub 2006 Oct 26. PMID:17134719 doi:10.1016/j.jmb.2006.10.075
  • Surace EI, Haipek CA, Gutmann DH. Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene function. Oncogene. 2004 Jan 15;23(2):580-7. PMID:14724586 doi:10.1038/sj.onc.1207142
  • Mani T, Hennigan RF, Foster LA, Conrady DG, Herr AB, Ip W. FERM domain phosphoinositide binding targets merlin to the membrane and is essential for its growth-suppressive function. Mol Cell Biol. 2011 May;31(10):1983-96. doi: 10.1128/MCB.00609-10. Epub 2011 Mar , 14. PMID:21402777 doi:10.1128/MCB.00609-10
  • Pearson MA, Reczek D, Bretscher A, Karplus PA. Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell. 2000 Apr 28;101(3):259-70. PMID:10847681

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