Protein tyrosine phosphatase-1B regulates the tyrosine phosphorylation of the adapter Grb2-associated binder 1 (Gab1) in the retina

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.

Regulation of Phosphoinositide Levels in the Retina by Protein Tyrosine Phosphatase 1B and Growth Factor Receptor-Bound Protein 14

“…Our model prediction also revealed the existence of a salt bridge between pGrb14-H350 and PTP1B-D181. The PTP1B-D181A mutant has previously been used as a substrate trap and identified several PTP1B substrates [ 24 , 25 , 26 , 27 ]. This mutant accesses the substrate but is unable to release and dephosphorylate the pTyr on the substrates [ 24 ].…”

Connection between Gab1 Polymorphisms and cholangiocarcinoma patients prognosis

“…Gab1 protein is encoded by the Gab1 gene, which is located on human chromosome 4q31.1 [12]. Evidence has revealed that Gab1 contains a Met-bind domain, an NH2-terminal pleckstrin homology (PH) domain, 16 potential tyrosine phosphorylation sites and 3 proline-rich sequences [13,14]. Gab1 has been proved to be implicated in a variety of biological activities, such as signal transduction of various factors, development of different organs, and cell proliferation and differentiation [15][16][17].…”

2-Acyl-3-carboxyl-tetrahydroisoquinoline Derivatives: Mixed-Type PTP1B Inhibitors without PPARγ Activation

“…18,22) Furthermore, PTP1B has been implicated in tumorigenesis, podocyte injury, endothelial dysfunction, and retinal light damage. 18,22,[33][34][35] In the present study, to identify a carboxyl-type PTP1B inhibitor without PPARγ activation that is suitable for oral and parenteral use, a novel series of 2-acyl-3-carboxyl-tetra-hydroisoquinoline derivatives were synthesized and evaluated. Structure-activity relationships were discussed and (S)-2-{(E)-3-furan-2-ylacryloyl}-7-[(2E,4E)-5-(2,4,6-trifluorophenyl)penta-2,4-dienyloxy]-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid (compound 17u) was selected for further evaluations.…”