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A potential role for nuclear factor of activated T-cells in receptor tyrosine kinase and G-protein-coupled receptor agonist-induced cell proliferation.

ABSTRACT: We have studied the role of nuclear factor of activated T-cells (NFAT) transcription factors in the induction of vascular smooth muscle cell (VSMC) growth by platelet-derived growth factor-BB (PDGF-BB) and thrombin, the receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) agonists, respectively. NFATc1 but not NFATc2 or NFATc3 was translocated from the cytoplasm to the nucleus upon treatment of VSMCs with PDGF-BB or thrombin. Translocation of NFATc1 was followed by an increase in NFAT-DNA binding activity and NFAT-dependent reporter gene expression. Cyclosporin A (CsA), a potent and specific inhibitor of calcineurin, a calcium/calmodulin-dependent serine phosphatase involved in the dephosphorylation and activation of NFATs, blocked NFAT-DNA binding activity and NFAT-dependent reporter gene expression induced by PDGF-BB and thrombin. CsA also completely inhibited PDGF-BB- and thrombin-induced VSMC growth, as measured by DNA synthesis and cell number. In addition, forced expression of the NFAT-competing peptide VIVIT for calcineurin binding significantly attenuated the DNA synthesis induced by PDGF-BB and thrombin in VSMCs. Together, these findings for the first time demonstrate a role for NFATs in RTK and GPCR agonist-induced growth in VSMCs.

SUBMITTER: Yellaturu CR

PROVIDER: S-EPMC1222985 | biostudies-other | 2002 Nov

REPOSITORIES: biostudies-other

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Project description:BackgroundErbB4/HER4 is a unique member of the ErbB family of receptor tyrosine kinases concerning its activation of anti-proliferative JAK2-STAT5 pathway when stimulated by ligand Neuregulin (NRG). Activation of this pathway leads to expression of genes like ?-casein which promote cell differentiation. Recent experimental studies on mouse HC11 mammary epithelial cells stimulated by ligand Neuregulin (NRG) showed a time-dependent switching behavior in the ?-casein expression. This behavior cannot be explained using currently available mechanistic models of the JAK-STAT pathway. We constructed an improved mechanistic model which introduces two crucial modifications to the canonical HER4-JAK2-STAT5 pathway based on literature findings. These modifications include competitive HER4 heterodimerization with other members of the ErbB family and a slower JAK2 independent activation STAT5 through HER4. We also performed global sensitivity analysis on the model to test the robustness of the predictions and parameter combinations that are sensitive to the outcome.ResultsOur model was able to reproduce the time-dependent switching behavior of ?-casein and also establish that the modifications mentioned above to the canonical JAK-STAT pathway are necessary to reproduce this behavior. The sensitivity studies show that the competitive HER4 heterodimerization reactions have a profound impact on the sensitivity of the pathway to NRG stimulation, while the slower JAK2-independent pathway is necessary for the late stage promotion of ?-casein mRNA transcription. The difference in the time scales of the JAK-dependent and JAK-independent pathways was found to be the main contributing factor to the time-dependent switch. The transport rates controlling activated STAT5 dimer nuclear import and ?-casein mRNA export to cytoplasm affected the time delay between NRG stimulation and peak ?-casein mRNA activity.ConclusionThis study highlights the effect of competitive and parallel reaction pathways on both short and long-term dynamics of receptor-mediated signaling. It provides robust and testable predictions of the dynamical behavior of the HER4 mediated JAK-STAT pathway which could be useful in designing treatments for various cancers where this pathway is activated/altered.

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A potential role for nuclear factor of activated T-cells in receptor tyrosine kinase and G-protein-coupled receptor agonist-induced cell proliferation.

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