title: Spatial and temporal aspects and the interplay of Grb14 and protein tyrosine phosphatase-1B on the insulin receptor phosphorylation.
abstract: BACKGROUND
  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 are post-mitotic tissue, and insulin receptor (IR) activation is essential for retinal neuron survival. Retinal cells express protein tyrosine phosphatase-1B (PTP1B), which dephosphorylates IR and Grb14, a pseudosubstrate inhibitor of IR. This project asks the following major question: in retinal neurons, how does the IR overcome inactivation by PTP1B and Grb14?
  
  
  RESULTS
  Our previous studies suggest that ablation of Grb14 results in decreased IR activation, due to increased PTP1B activity. Our research propounds that phosphorylation in the 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 of Grb14 in diabetic type 1 Ins2Akita mouse retinas. Decreased retinal IR activation has previously been reported in this mouse line.
  
  
  CONCLUSIONS
  Our results suggest that phosphorylation status of the BPS region of Grb14 determines the positive or negative role it will play in IR signaling.
authors.affiliation: Departments of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. raju-rajala@ouhsc.edu.
authors.forename: Raju V S
authors.initials: RV
authors.lastname: Rajala
authors.forename: Devaraj K
authors.initials: DK
authors.lastname: Basavarajappa
authors.forename: Radhika
authors.initials: R
authors.lastname: Dighe
authors.forename: Ammaji
authors.initials: A
authors.lastname: Rajala
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism*; D012374:Rod Cell Outer Segment / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490977:Grb14 protein, mouse; C490976:Grb14 protein, rat; D011506:Proteins; D011972:Receptor, Insulin; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse