title: Phosphorylated Grb14 is an endogenous inhibitor of retinal protein tyrosine phosphatase 1B, and light-dependent activation of Src phosphorylates Grb14.
abstract: 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.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd., Oklahoma City, OK 73104, USA.
authors.forename: Devaraj K
authors.initials: DK
authors.lastname: Basavarajappa
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Gupta
authors.forename: Radhika
authors.initials: R
authors.lastname: Dighe
authors.forename: Ammaji
authors.initials: A
authors.lastname: Rajala
authors.forename: Raju V S
authors.initials: RV
authors.lastname: Rajala
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003624:Darkness; D004789:Enzyme Activation; D008027:Light; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D012160:Retina / Q000201:enzymology* / Q000502:physiology; D012243:Rhodopsin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490977:Grb14 protein, mouse; D011506:Proteins; D012243:Rhodopsin; D011972:Receptor, Insulin; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1