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autophosphorylation sites of growth factor receptors. This small protein  is essential for multiple cellular functions such as embryonic development and cell proliferation. Moreover, 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.  

===MAP kinases pathway===

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"/>

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 tyrosine 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.

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