Department of Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA.
Mol Cell Biol. 2011 Oct;31(19):3975-87. doi: 10.1128/MCB.05659-11. Epub 2011 Jul 26.
Growth factor receptor-bound protein 14 (Grb14) is an adapter protein implicated in receptor tyrosine kinase signaling. Grb14(-/-) studies highlight both the positive and negative roles of Grb14 in receptor tyrosine kinase signaling in a tissue-specific manner. In this study, we made a novel finding that Grb14 inhibits the activity of PTP1B, the major negative regulator of insulin receptor (IR) signaling, in a phosphorylation-regulated manner. Phosphorylation of Tyr-347 in the BPS domain of Grb14 is critical for interaction with PTP1B, resulting in the competitive inhibition of PTP1B activity. We also found that rhodopsin-regulated Src kinase activation in retina leads to the phosphorylation of Grb14. Further, ablation of Grb14 resulted in significantly elevated retinal PTP1B activity in vivo. PTP1B is known to be regulated by oxidation, glutathionylation, phosphorylation, and SUMOlyation, and our study for the first time demonstrates the inhibition of PTP1B activity in vivo by protein molecule Grb14 in a tissue-specific manner.
生长因子受体结合蛋白 14（Grb14）是一种衔接蛋白，参与受体酪氨酸激酶信号转导。Grb14（-/-）研究强调了 Grb14 在组织特异性受体酪氨酸激酶信号转导中具有积极和消极的作用。在这项研究中，我们有一个新的发现，Grb14 通过磷酸化调节的方式抑制蛋白酪氨酸磷酸酶 1B（PTP1B）的活性，PTP1B 是胰岛素受体（IR）信号的主要负调控因子。Grb14 的 BPS 结构域中的 Tyr-347 磷酸化对于与 PTP1B 的相互作用至关重要，导致 PTP1B 活性的竞争性抑制。我们还发现视网膜中的视紫红质调节的Src 激酶激活导致 Grb14 的磷酸化。此外，Grb14 的缺失导致体内视网膜 PTP1B 活性显著升高。PTP1B 的活性已知受到氧化、谷胱甘肽化、磷酸化和 SUMO 化的调节，我们的研究首次证明了 Grb14 以组织特异性的方式在体内抑制 PTP1B 的活性。
