Gab Adapter Proteins as Therapeutic Targets for Hematologic Disease

Figure 2

Gab2 interactions with binding partners. Diagram shows generic Gab adapter docked at the plasma membrane by the PH domain. Interactions with p85 and SHP-2 are involved in Akt and Erk activation respectively. Binding of receptor tyrosine kinases to their receptive ligands triggers the kinase activity of the cytoplasmic domain of the receptor. The receptor becomes phosphorylated on tyrosine residues. Docking proteins such as Grb2 contain SH2 domains that bind to the phosphotyrosine residues of the activated receptor. Grb2-Gab interacts through the SH3 domains and activates downstream signaling pathways, PI-3K/Akt and SHP2/Erk. Grb-2 can bind to SOS via N-terminal SH3 domain while the C-terminal SH3 domains are used for its interaction with Gab proteins. SOS-1 has been known to associate with Grb2, leading to its autophosphorylation. This complex gets translocated to the activated receptor where it then associates with Ras. As Ras gets activated it induces the downstream ERK/MAPK pathway. Alternatively, stimuli from growth factors like EGF, VEGF, and so forth, causes binding of Gab2 to Grb2. This then leads to recruitment of SHP2, that binds to phosphorylated tyrosine residues on Gab, and in turn activates ERK/MAPK signaling. Negative feedback by serine phosphorylation of Gab at S160 by Akt and S623 by Erk (block arrows) plays an important role in control of function and signaling of Gabs.