Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2004, PMID: 14604996

Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells.

Neid, Matthias; Datta, Kaustubh; Stephan, Susann; Khanna, Ila; Pal, Soumitro; Shaw, Leslie; White, Morris; Mukhopadhyay, Debabrata

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), the critical molecule in tumor angiogenesis, is regulated by different stimuli, such as hypoxia and oncogenes, and also by growth factors. Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor (IGF-IR) regulates VPF/VEGF expression. Insulin receptor substrate-1 and -2 (IRS-1 and IRS-2), two major downstream molecules of IGF-1R, are known to be important in the genesis of diabetes. In this study, we have defined a new role of IRS in angiogenesis. Both of the IRS proteins modulate VPF/VEGF expression in pancreatic cancer cells by different mechanistic pathways. The Sp1-dependent VPF/VEGF transcription is regulated mainly by IRS-2. Protein kinase C-zeta (PKC-zeta) plays a central role in VPF/VEGF expression and acts as a switching element. Furthermore, we have also demonstrated that the phosphatidylinositol 3-kinase pathway, but not the Ras pathway, is a downstream event of IRS proteins for VPF/VEGF expression in AsPC-1 cells. Interestingly, like renal cancer cells, in AsPC-1 cells PKC-zeta leads to direct Sp1-dependent VPF/VEGF transcription; in addition, it also promotes a negative feedback loop to IRS-2 that decreases the association of IRS-2/IGF-1R and IRS-2/p85. Taken together, our results show that in AsPC-1 pancreatic carcinoma cells, Sp1-dependent VPF/VEGF transcription is controlled by IGF-1R signaling through IRS-2 proteins and modulated by a negative feedback loop of PKC-zeta to IRS-2. Our data also suggest that IRS proteins, which are known to play crucial roles in IGF-1R signaling, are also important mediators for tumor angiogenesis.

Diseases/Pathways annotated by Medline MESH: Adenocarcinoma, Neovascularization, Pathologic, Pancreatic Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

vascular permeability factor/vascular ⊣ protein kinase C-zeta: " Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells "

VPF/VEGF → IGF-IR: " Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor ( IGF-IR ) regulates VPF/VEGF expression "

VPF/VEGF → insulin-like: " Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor ( IGF-IR ) regulates VPF/VEGF expression "

VPF/VEGF → Sp1: " The Sp1 dependent VPF/VEGF transcription is regulated mainly by IRS-2 "

VPF/VEGF → IRS-2: " The Sp1 dependent VPF/VEGF transcription is regulated mainly by IRS-2 "

VPF/VEGF → Sp1: " Interestingly, like renal cancer cells, in AsPC-1 cells PKC-zeta leads to direct Sp1 dependent VPF/VEGF transcription ; in addition, it also promotes a negative feedback loop to IRS-2 that decreases the association of IRS-2/IGF-1R and IRS-2/p85 "

VPF/VEGF → Sp1: " Taken together, our results show that in AsPC-1 pancreatic carcinoma cells, Sp1 dependent VPF/VEGF transcription is controlled by IGF-1R signaling through IRS-2 proteins and modulated by a negative feedback loop of PKC-zeta to IRS-2 "

VPF/VEGF — IGF-1R: " Taken together, our results show that in AsPC-1 pancreatic carcinoma cells, Sp1 dependent VPF/VEGF transcription is controlled by IGF-1R signaling through IRS-2 proteins and modulated by a negative feedback loop of PKC-zeta to IRS-2 "

Manually curated Databases

  • OpenBEL Selventa BEL large corpus: SP1 → PRKCZ (increases, PRKCZ Activity, SP1 Activity)
    Evidence: Modified assertion
  • OpenBEL Selventa BEL large corpus: PRKCZ → PRKCZ (directlyIncreases, PRKCZ Activity)
    Evidence: PDK-1 is a downstream molecule of PI3K, which activates among many others, PKC-z (37). This protein kinase is a member of the atypical PKCs. Unlike conventional or novel PKCs, it does not require diacylglycerol or phorbol esters for its activation and its function is Ca2+ independent (38). To achieve catalytic potential, PKC-z needs to be phosphorylated on threonine 410 (T410) through PDK-1 (37, 39).
  • NCI Pathway Database IGF1 pathway: PDK1 (PDPK1) → PKC zeta (PRKCZ) (modification, activates)
    Evidence: assay
In total, 1 gene pairs are associated to this article in curated databases