Sandbox Reserved 1124: Difference between revisions
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===The SH2 domain=== | === The SH2 domain === | ||
This domain is very essential for the function of Grb2. In fact, <scene name='71/719865/Sh2domains/1'>the SH2 domain</scene> of Grb2 enables the interaction with receptors, scaffold proteins, tyrosine kinases but also with other adaptor proteins. Indeed, Shc is an intermediate between some receptors and Grb2. | This domain is very essential for the function of Grb2. In fact, <scene name='71/719865/Sh2domains/1'>the SH2 domain</scene> of Grb2 enables the interaction with receptors, scaffold proteins, tyrosine kinases but also with other adaptor proteins. Indeed, Shc is an intermediate between some receptors and Grb2. | ||
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===The N-Terminal SH3 domain=== | === The N-Terminal SH3 domain === | ||
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===The C-Terminal SH3 domain=== | === The C-Terminal SH3 domain === | ||
<scene name='71/719865/C-terminal_sh3_domains/1'>The C-terminal SH3 domain</scene> goes from the amino acid 156 to 215. The role of this domain is little known. But it has been shown that, for a stable complex formation, the C-Terminal SH3 domain has to recognize a 13 residues sequence with the following motif: P-x-x-x-R-x-x-K-P. Sos contains this sequence, as well as Gab1, which also binds to Grb2. The interaction of Grb2 with Gab1 has been demonstrated with precipitation experiments. <ref >PMID: 11314042</ref> | <scene name='71/719865/C-terminal_sh3_domains/1'>The C-terminal SH3 domain</scene> goes from the amino acid 156 to 215. The role of this domain is little known. But it has been shown that, for a stable complex formation, the C-Terminal SH3 domain has to recognize a 13 residues sequence with the following motif: P-x-x-x-R-x-x-K-P. Sos contains this sequence, as well as Gab1, which also binds to Grb2. The interaction of Grb2 with Gab1 has been demonstrated with precipitation experiments. <ref >PMID: 11314042</ref> | ||
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== Function == | == Function == | ||
===MAP kinases pathway=== | === MAP kinases pathway === | ||
In the cytosol, Grb2 is bound to the guanine nucleotide exchange factor SOS-1 via its SH3 domain. Then, this complexe is recruited to the plasmic membrane to be close the Ras protein. To help Grb2 binds the phosphorylated tyrosines of the EGFR via its two SH2 domains. The Ras protein is a small GTPase which is in an inactive state when it is bound to GDP. However, the exchange of GDP for GTP actives it allowing the bond and the activation of Raf 1, a serine/threonine protein kinase. A cascade of kinase phosphorylation is then initiated. Indeed, Raf 1 phosphorylates MEK1 or MEK 2 which in turn phosphorylate ERK1 or ERK2. Finally, these MAP kinases allow the translocation of transcription factors to the nucleus and their phosphorylation. Such as STAT 1 or Elk-1.<ref name="A"/> | In the cytosol, Grb2 is bound to the guanine nucleotide exchange factor SOS-1 via its SH3 domain. Then, this complexe is recruited to the plasmic membrane to be close the Ras protein. To help Grb2 binds the phosphorylated tyrosines of the EGFR via its two SH2 domains. The Ras protein is a small GTPase which is in an inactive state when it is bound to GDP. However, the exchange of GDP for GTP actives it allowing the bond and the activation of Raf 1, a serine/threonine protein kinase. A cascade of kinase phosphorylation is then initiated. Indeed, Raf 1 phosphorylates MEK1 or MEK 2 which in turn phosphorylate ERK1 or ERK2. Finally, these MAP kinases allow the translocation of transcription factors to the nucleus and their phosphorylation. Such as STAT 1 or Elk-1.<ref name="A"/> | ||
Moreover, the SH2 domain recognizes the C-terminal domain of FAK (Focal Adhesion Kinase) called the focal adhesion targeting region (FAT) when its tyrosine 925 on the first helix is phosphorylated. But, this tyrosine contains the pY925 motif and is not a β-turn structure. Thus, an adaptation of this tyrosine on the SH2 domain is possible. To conclude, the interaction between Grb2 and FAK leads to the activation of the Ras-MAPK pathway. | Moreover, the SH2 domain recognizes the C-terminal domain of FAK (Focal Adhesion Kinase) called the focal adhesion targeting region (FAT) when its tyrosine 925 on the first helix is phosphorylated. But, this tyrosine contains the pY925 motif and is not a β-turn structure. Thus, an adaptation of this tyrosine on the SH2 domain is possible. To conclude, the interaction between Grb2 and FAK leads to the activation of the Ras-MAPK pathway. | ||
===PI3K/AKT pathway=== | === PI3K/AKT pathway === | ||
In epithelial cells, an adaptator called Gab1 binds the carboxyl terminal SH3 domain of Grb2. This causes the activation of PI3K/AKT pathway.<ref name="A"/> | In epithelial cells, an adaptator called Gab1 binds the carboxyl terminal SH3 domain of Grb2. This causes the activation of PI3K/AKT pathway.<ref name="A"/> | ||
===T cells=== | === T cells === | ||
When TCR are stimulated, the membrane protein called p36-38 is phosphorylated in the T cells. Then, the phosphorylated tyrosines bind the SH2 domains of Grb2 whereas the SH3 domains are bound to Vav proteins. These interactions allow the T cell proliferation, the calcium flux in these cells and the MAP kinase activation.<ref name="A"/> | When TCR are stimulated, the membrane protein called p36-38 is phosphorylated in the T cells. Then, the phosphorylated tyrosines bind the SH2 domains of Grb2 whereas the SH3 domains are bound to Vav proteins. These interactions allow the T cell proliferation, the calcium flux in these cells and the MAP kinase activation.<ref name="A"/> | ||
