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Raju V S Rajala, Ammaji Rajala; The Spatial and Temporal Activation of the Retinal Insulin Receptor: Role of Grb14 and PTP1B. Invest. Ophthalmol. Vis. Sci. 2014;55(13):408.
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Retinal cells are post-mitotic tissue. Insulin receptor (IR) activation is essential for retinal neuron survival. Growth factor receptor-bound protein 14 (Grb14) is an adapter protein implicated in receptor tyrosine kinase signaling. Grb14 knockout studies highlight both the positive and negative roles of Grb14 in receptor tyrosine kinase signaling, in a tissue specific manner. Retinal cells express protein tyrosine phosphatase-1B (PTP1B), which dephosphorylates IR and Grb14, a pseudosubstrate inhibitor of the IR. Thus, the major question remains: in retinal neurons, how does the IR overcome inactivation by PTP1B and Grb14?
Wild type, PTP1B-/-, Grb14-/-, and diabetic type 1 Ins2Akita mice were used in this study. Retinal IR kinase activity, PTP1B activity and IR phosphorylation were measured.
Our studies suggest that ablation of Grb14 results in decreased IR activation due to increased PTP1B activity. Our research propounds that a phosphorylated BPS region of Grb14 inhibits PTP1B activity, thereby promoting IR activation. We propose a model in which phosphorylation of the BPS region of Grb14 is the key element in promoting IR activation, and failure to undergo phosphorylation on Grb14 leads to both PTP1B and Grb14 exerting their negative roles in IR. Consistent with this hypothesis, we found decreased phosphorylation on Grb14 in diabetic type 1 Ins2Akita mouse retinas, and a decreased retinal IR activation has previously been reported in this mouse line.
Our results suggest that the phosphorylation status of the BPS region of Grb14 determines the positive or negative role it will play in IR signaling. Further, activators of Grb14 phosphorylation may have therapeutic potential to protect the dying retinal neurons in retinal degenerative diseases.
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