Sandbox Reserved 1124: Difference between revisions

----

mettre une photo de monomère

Grb2 (Growth factor receptor-bound protein 2) is an adaptator protein implicated in signal transduction such as the Ras signalling pathway. This protein implied in signal transduction pathways is essential for multiple cellular functions such as: embryonic development and cell proliferation. Grb2 can be found in the cytosol, the nucleus and the plasmic membrane.

The relevance of Grb2 has been enlightened thanks to studies on ''Caenorhabditis elegans''. Sem-5, an homologue of Grb2, was found to be implied in the Let-60 pathway, an homologue of Ras.

The gene which codes the Grb2 protein is located on the seventeenth chromosome. It is composed of five exons, ranging from 78 to 186 bp, and four introns from 1 to 7 kb. It is transcribed into 2 mRNA arising from alternative splicing. Thus, there are two protein isoforms. The RNA coding for the second isoform has lost the exon of the 3' coding region, thus this isoform lacks the residues from 59 to 100 in the mature Grb2. In fact, it is a deletion in the amino-terminal part of the SH2 domain. Therefore, the function is modified because this domain cannot bind the phosphorylated tyrosine.<ref name="A"/>

Grb2 is a small protein of 217 residues with a molecular mass of about 25,206 Da and composed of three remarkable domains : a single SH2 (Src Homology 2) domain (60 to 152 pdb) flanked by two conserved SH3 domains (respectively 1 to 58 and 156 to 215 pdb)<ref name="A">Gagani Athauda, Donald P Bottaro Atlas of Genetics and Cytogenetics in Oncology and Haematology (2007)[http://atlasgeneticsoncology.org/Genes/GRB2ID386ch17q25.html]</ref>. The two SH3 domains bind proline-rich regions of other proteins and enable the interaction with the Sos protein (Son of Sevenless, guanine nucleotide exchange factor). Moreover it has no catalytic domain. The Grb2 protein can exist in two states : monomeric or dimeric. However, only the monomeric Grb2 conformation is able to bind SOS protein and regulate MAP kinases. In this case, the dimeric Grb2 plays the role of an inhibitor. In fact, the dimer dissociation allows the phosphorylation of Grb2 160 tyrosine and the bond of SH2 domain with phosphorylated tyrosines. To conclude, the switch between these two conformations controls the MAP kinase activity.

The determination of the crystallographic structure enabled the observation of the junction between the SH3 and SH2 domains. It allows the two adjacent faces of the SH3 domains to be closer. This association is strenghtened by Van der Waals interaction. Nevertheless, the proline-rich peptides can still bind to SH3 domains. And when the SH2 domain of Grb2 binds to a receptor, the ability of the SH3 domains to interact with Sos motifs does not change.  

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"/>