Sandbox Reserved 1124: Difference between revisions
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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 to 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 | 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 to 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 phosphorylates ERK1 or ERK2. Finally, these MAP kinases allow the translocation of transcription factors, such as STAT 1 or Elk-1, to the nucleus and their phosphorylation.<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.<ref >PMID: 20124721</ref> | 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.<ref >PMID: 20124721</ref> | ||
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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 of p36-38 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"/> | ||
== Implication of Grb2 disruption in various diseases == | == Implication of Grb2 disruption in various diseases == | ||
Grb2 is an intermediate protein and recruits signalling molecules to form complexes. These signalling complexes cause cellular responses like cellular proliferation or invasion which can have an impact in cancer. Grb2 can also occur in many other stages of the cancer progression : it can lead to tumorigenesis.<ref>DOI:10.1517/14728222.12.8.1021</ref> Moreover, the phosphorylation of the 160 | Grb2 is an intermediate protein and recruits signalling molecules to form complexes. These signalling complexes cause cellular responses like cellular proliferation or invasion which can have an impact in cancer. Grb2 can also occur in many other stages of the cancer progression : it can lead to tumorigenesis.<ref>DOI:10.1517/14728222.12.8.1021</ref> Moreover, the phosphorylation of the tyrosine 160 on Grb2 has been observed in many human cancers such as prostate, colon or breast cancers and the switch between the dimeric and monomeric conformations regulates the cancer progression.<ref name="anaïs">PMID: 26234419</ref> | ||
Several mutations in the SH2 domain can cause human diseases such as Noonan syndrome or basal cell carcinoma. For example, it can | Several mutations in the SH2 domain can cause human diseases such as Noonan syndrome or basal cell carcinoma. For example, it can induce a suppression of phosphotyrosine dependent interactions due to a mutation of the arginin residue at position 5 of the βB strand in the SH2 domain.<ref name="Kousik"/> This suppression can lead to a non-functioning signalling pathway. | ||
Grb2 is implied in Alzheimer's disease. It is an adaptor protein of AbetaPP (amyloid-beta protein precursor), a protein matured by proteases along the endosomal lysosomal pathway. In Alzheimer's disease patient neurons, Grb2 is overexpressed and concentrates in the neuronal cell bodies and more precisely in late endosomes, bringing AbetaPP proteins with it. The sequestration of AbetaPP in late endosomes avoids its release and causes | Grb2 is implied in Alzheimer's disease. It is an adaptor protein of AbetaPP (amyloid-beta protein precursor), a protein matured by proteases along the endosomal lysosomal pathway. In Alzheimer's disease patient neurons, Grb2 is overexpressed and concentrates in the neuronal cell bodies and more precisely in late endosomes, bringing AbetaPP proteins with it. The sequestration of AbetaPP in late endosomes avoids its release and causes an abnormal increasing of its intracellular concentration.<ref>PMID: 20164575</ref> | ||
== References == | == References == | ||
