Sandbox Reserved 705: Difference between revisions

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Phosphorylation of a C-terminal threonine by Rho kinase and binding to phosphatidylinositol 4,5-bisphosphate and protein partners, is necessary for full activation of ERM proteins <ref>PMID:14993232</ref>. 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.
Phosphorylation of a C-terminal threonine by Rho kinase and binding to phosphatidylinositol 4,5-bisphosphate and protein partners, is necessary for full activation of ERM proteins <ref>PMID:14993232</ref>. 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.


Merlin shares certain properties with the ERM family : they both have a subcellular localization to cortical action structures and both bind to the integral membrane hyaluronic acid receptor CD44.<ref>PMID:9330869</ref>
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 <ref>PMID:9330869</ref> and E-cadherin <ref>PMID:12695331</ref>.
However Merlin-1 has some properties not shared with ERM proteins.  
However Merlin-1 has some properties not shared with ERM proteins.  


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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<ref name= "utile2" />.
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<ref name= "utile2" />.
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 a closed conformation and is able to promote nuclear translocation and inhibt growth<ref>PMID:22482125</ref>.
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 a closed conformation and is able to promote nuclear translocation and inhibt growth<ref>PMID:22482125</ref>.
'''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.Ser-10 and Ser-518 phosphorylation by PKA and/or PAK trigger the "closed" complex <ref>PMID:18071304</ref>.. Further, phosphomimetic mutants of these sites impair merlin-1 tumor suppression functions and these mutants directly interact with other partners in cells, such as ezrin.28 Binding partners for ERM proteins include each other, and selected adhesion proteins and adapters that direct association with membrane-spanning proteins. For example, the C-terminal domains of the EBP50 and E3KARP members of the NHERF (Na+-H+ Exchanger Regulatory Factor) family bind to ezrin and merlin, and link ERMs to membrane proteins such as NHE3 and CTFR through the agency of their PDZ domains.29 In addition, ERM proteins and merlin also directly bind to adhesion receptors, including NHERF,30 CD44,31 and E-cadherin.7'''<ref name="utile2"/>
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 <ref name="utile" />. Ser-10 and Ser-518 phosphorylation by protein kinase A (PKA) and/or p21-activated kinase(PAK) trigger the "closed" complex <ref>PMID:18071304</ref>.  


Conversely, Merlin's dephosphorylated and closed form is active and functions in tumour suppression and contact inhibition.
Conversely, Merlin's dephosphorylated and closed form is active and functions in tumour suppression and contact inhibition.
  Phosphorylation by PAK and PKA at Ser 518 renders the protein inactive in its putatively open form. ERM, Ezrin/Radixin/Moesin; FERM, 4.1 protein/Ezrin/Radixin/Moesin; MYPT1, myosin phosphatase targeting subunit 1; PAK, p21-activated kinase; PKA, protein kinase A; PIP2, phosphatidylinositol 4,5-bisphosphate; RhoK, Ras homologue gene family, member K.
  Phosphorylation by PAK and PKA at Ser 518 renders the protein inactive in its putatively open form. ERM, Ezrin/Radixin/Moesin; FERM, 4.1 protein/Ezrin/Radixin/Moesin; MYPT1, myosin phosphatase targeting subunit 1;  
===CD44===
===CD44===
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. Indeed, CD44 is a receptor presents in the TA3 carcinome mammaire cells and Tr6BC1 schwannoma cells and HA allows their growth.
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. Indeed, CD44 is a receptor presents in the TA3 carcinome mammaire cells and Tr6BC1 schwannoma cells and HA allows their growth.
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