Abstract
BackgroundGab1 (Grb2-associated binder 1) is a key coordinator that belongs to the insulin receptor substrate-1 like family of adaptor molecules and is tyrosine phosphorylated in response to various growth factors, cytokines, and numerous other molecules. Tyrosine phosphorylated Gab1 is able to recruit a number of signaling effectors including PI3K, SHP2 and PLC-γ. In this study, we characterized the localization and regulation of tyrosine phosphorylation of Gab1 in the retina.ResultsOur immuno localization studies suggest that Gab1 is expressed in rod photoreceptor inner segments. We found that hydrogen peroxide activates the tyrosine phosphorylation of Gab1 ex vivo and hydrogen peroxide has been shown to inhibit the protein tyrosine phosphatase PTP1B activity. We found a stable association between the D181A substrate trap mutant of PTP1B and Gab1. Our studies suggest that PTP1B interacts with Gab1 through Tyrosine 83 and this residue may be the major PTP1B target residue on Gab1. We also found that Gab1 undergoes a light-dependent tyrosine phosphorylation and PTP1B regulates the phosphorylation state of Gab1. Consistent with these observations, we found an enhanced Gab1 tyrosine phosphorylation in PTP1B deficient mice and also in retinas treated ex vivo with a PTP1B specific allosteric inhibitor.ConclusionsOur laboratory has previously reported that retinas deficient of PTP1B are resistant to light damage compared to wild type mice. Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well. In summary, our data suggest that PTP1B regulates the phosphorylation state of retinal Gab1 in vivo.
Highlights
Grb2-associated binding protein 1 (Gab1) (Grb2-associated binder 1) is a key coordinator that belongs to the insulin receptor substrate-1 like family of adaptor molecules and is tyrosine phosphorylated in response to various growth factors, cytokines, and numerous other molecules
The results indicate that Gab1 is present in Band II and rest of the retina fractions and very low levels of Gab1 is present in ROS (Figure 2B)
Our laboratory has previously reported that retinas deficient of protein tyrosine phosphatase-1B (PTP1B) are resistant to light damage compared to wild type mice [61]
Summary
Gab (Grb2-associated binder 1) is a key coordinator that belongs to the insulin receptor substrate-1 like family of adaptor molecules and is tyrosine phosphorylated in response to various growth factors, cytokines, and numerous other molecules. Gab (Grb2-assoicated binder 1) is a member of a small group of scaffolding adapters that includes Drosophila melanogaster Dos (Daughter of Sevenless), the Caneorhabditis elegans homolog Soc (Suppressor-Of Clear), and mammalian Gab and Gab3 [1,2,3,4,5,6,7,8] These proteins contain an amino-terminal PH domain, several proline-rich sequences, and multiple binding sites for SH2-domain containing proteins. Mutation in the p85-binding sites of Gab was found to impair the ability of IL-3 to activate Akt and to induce cell growth [18] These studies clearly suggest that Gabp interaction plays an important role in activating the PI3K/Akt pathway in mammalian cells. The EGF-dependent positive feedback loop is negatively regulated by SHP2 by dephosphorylating Gab1-p85 binding sites, thereby terminating the Gab1-P3K positive loop [23]
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