RGD Reference Report - PDGF- and insulin/IGF-1-specific distinct modes of class IA PI 3-kinase activation in normal rat retinas and RGC-5 retinal ganglion cells. - Rat Genome Database

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PDGF- and insulin/IGF-1-specific distinct modes of class IA PI 3-kinase activation in normal rat retinas and RGC-5 retinal ganglion cells.

Authors: Biswas, SK  Zhao, Y  Nagalingam, A  Gardner, TW  Sandirasegarane, L 
Citation: Biswas SK, etal., Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3687-98. Epub 2008 Apr 17.
RGD ID: 4108491
Pubmed: PMID:18421086   (View Abstract at PubMed)
DOI: DOI:10.1167/iovs.07-1455   (Journal Full-text)

PURPOSE: To compare PDGF- and insulin/IGF-1-induced class I(A) PI 3-kinase/Akt survival signaling in normal retinas and retinal ganglion cells (RGCs). METHODS: Normal rat retinas and RGC-5 cells were used for (1) immunohistochemical and immunoblot studies to detect PDGF receptor (PDGFR) subtypes and (2) immunoprecipitation, immunoblot, and in vitro lipid kinase assays to determine basal and PDGF-induced class I(A) PI 3-kinase/Akt survival signaling, in comparison with insulin or IGF-1 responses. Furthermore, RGC-5 cells were exposed to broad-spectrum (LY294002) or p110 isoform-selective (PI-103) PI 3-kinase inhibitors (versus Akt inhibitor) to assess the consequent effects on Akt phosphorylation, caspase-3/PARP cleavage, apoptotic phenotype, and cell viability, as a function of serum trophic factors. RESULTS: PDGFR-alpha and -beta immunoreactivity was observed in rat retinal Muller cells and in the RGC layer and blood vessels, respectively. In addition, PDGFR-alpha and -beta protein expression was observed in RGC-5 cells. Both retinas and RGC-5 cells exhibited a similar pattern of subunit-specific basal class I(A) PI 3-kinase activity, which was stimulated in a temporal and signal-specific manner by PDGF and insulin/IGF-1. Furthermore, RGC-5 cells showed PDGFR-alpha/beta tyrosine phosphorylation that induced the p85alpha regulatory subunit to activate p110alpha/beta-associated class I(A) PI 3-kinase, which in turn enhanced Akt phosphorylation. Exposure of serum-deprived RGC-5 cells to PI 3-kinase or Akt inhibitors increased susceptibility to apoptotic phenotype as revealed by caspase-3 and PARP cleavage. CONCLUSIONS: The present findings provide direct evidence of two distinct modes of retinal class I(A) PI 3-kinase activation that occurs in response to PDGF receptor and insulin/IGF-1 receptor stimulation. PDGF-induced PI 3-kinase/PIP3/Akt axis may provide new therapeutic approaches to ameliorate cell death in diabetic retinopathy and other retinal neurodegenerations.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to growth factor  IEP 4108491PDGFRGD 

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Pdgfra  (platelet derived growth factor receptor alpha)
Pdgfrb  (platelet derived growth factor receptor beta)
Pik3r1  (phosphoinositide-3-kinase regulatory subunit 1)


Additional Information