scholarly journals PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation

2003 ◽  
Vol 162 (2) ◽  
pp. 281-291 ◽  
Author(s):  
Jill K. Slack-Davis ◽  
Scott T. Eblen ◽  
Maja Zecevic ◽  
Scott A. Boerner ◽  
Adel Tarcsafalvi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signal Transduction Pathway ◽  
Mapk Signaling ◽  
Growth Factor Signaling ◽  
Transduction Pathway ◽  
Mapk Activation ◽  
Src Signaling ◽  
Biological Responses ◽  
P21 Activated Kinase ◽  
A Site

Activation of the Ras–MAPK signal transduction pathway is necessary for biological responses both to growth factors and ECM. Here, we provide evidence that phosphorylation of S298 of MAPK kinase 1 (MEK1) by p21-activated kinase (PAK) is a site of convergence for integrin and growth factor signaling. We find that adhesion to fibronectin induces PAK1-dependent phosphorylation of MEK1 on S298 and that this phosphorylation is necessary for efficient activation of MEK1 and subsequent MAPK activation. The rapid and efficient activation of MEK and phosphorylation on S298 induced by cell adhesion to fibronectin is influenced by FAK and Src signaling and is paralleled by localization of phospho-S298 MEK1 and phospho-MAPK staining in peripheral membrane–proximal adhesion structures. We propose that FAK/Src-dependent, PAK1-mediated phosphorylation of MEK1 on S298 is central to the organization and localization of active Raf–MEK1–MAPK signaling complexes, and that formation of such complexes contributes to the adhesion dependence of growth factor signaling to MAPK.

Sprouty proteins: antagonists of endothelial cell signaling and more

2003 ◽  
Vol 90 (10) ◽  
pp. 586-590 ◽  
Author(s):  
Miguel Cabrita ◽  
Gerhard Christofori
Keyword(s):  
Growth Factor ◽  
Mapk Pathway ◽  
Medical Science ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dual Function ◽  
Vegf Receptor ◽  
Mapk Activation ◽  
Binding Partners

SummaryAmong many signaling pathways, receptor tyrosine kinases (RTKs) can activate the mitogen-activated protein kinase (MAPK) signaling pathway that subsequently leads to a variety of cellular changes, including proliferation, differentiation and motility. The regulation of growth factor signaling is complex, and various cell types respond differently to the same stimulus for reasons not entirely understood. The recent discovery in Drosophila of Sprouty (dSpry), an inhibitor of RTK-induced MAPK activation, provides clues to how these signals are regulated. In mammals, four orthologues of dSpry, Spry1-4, have been described, and in this review we discuss their functional characteristics. Mammalian Sprys, like dSpry, are ligand-induced feedback inhibitors of a number of growth factor receptors. In endothelial cells, upon fibroblast growth factor (FGF) receptor and vascular endothelial growth factor (VEGF) receptor activation, Sprys translocate to the plasma membrane and inhibit cell growth and proliferation. However, in epidermal growth factor (EGF)-stimulated cells, Sprys can enhance MAPK activation. In addition, Sprys have many binding partners, including different effectors of the MAPK activation pathway. The intersection point where Sprys interfere in the MAPK pathway as well as their interactions with other proteins may partly explain the dual, yet opposing roles, on growth factor-induced MAPK activation. Moreover, Sprys require tyrosine phosphorylation to interact with their binding partners, a prerequisite for their dual function. Hence, Sprys add another layer of complexity to the regulation of RTK-mediated signal transduction that begins to explain the variation in cellular responses to growth factors.This publication was partially financed by Serono Foundation for the Advancement of Medical Science.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.

scholarly journals BALB/c-3T3 fibroblasts resistant to growth inhibition by beta interferon exhibit aberrant platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor signal transduction.

1991 ◽  
Vol 11 (6) ◽  
pp. 3148-3154 ◽  
Author(s):  
L J Mundschau ◽  
D V Faller
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Signal Transduction Pathway ◽  
Platelet Derived Growth Factor ◽  
Fibroblast Growth ◽  
Transduction Pathway ◽  
Double Stranded Rna ◽  
Epidermal Growth

Several lines of evidence now exist to suggest an interaction between the platelet-derived growth factor (PDGF) growth-stimulatory signal transduction pathway and the beta interferon (IFN-beta) growth-inhibitory signal transduction pathway. The most direct examples are inhibition of PDGF-mediated gene induction and mitogenesis by IFN-beta and the effects of activators and inhibitors of the IFN-inducible double-stranded RNA-dependent eIF2 kinase on expression of PDGF-inducible genes. To further investigate the nature of this PDGF/IFN-beta interaction, we selected BALB/c-3T3 cells for resistance to growth inhibition by IFN-beta and analyzed the phenotypes of resulting clonal lines (called IRB cells) with respect to PDGF signal transduction. Although selected only for IFN resistance, the IRB cells were found to be defective for induction of growth-related genes c-fos, c-myc and JE in response to PDGF. This block to signal transduction was not due to loss or inactivation of PDGF receptors, as immunoprecipitation of PDGF receptors with antiphosphotyrosine antibodies showed them to be present at equal levels in the BALB/c-3T3 and IRB cells and to be autophosphorylated normally in response to PDGF. Furthermore, treatment with other peptide growth factors (PDGF-AA, fibroblast growth factor, and epidermal growth factor) also failed to induce c-fos, c-myc, or JE expression in IRB cells. All of these growth factors, however, were able to induce another early growth-related gene, Egr-1. The block to signaling was not due to a defect in inositol phosphate metabolism, as PDGF treatment induced normal calcium mobilization and phosphotidylinositol-3-kinase activation in these cells. Activation of protein kinase C by phorbol esters did induce c-fos, c-myc, and JE in IRB cells, indicating that signalling pathways distal to this enzyme remained intact. We have previously shown that IFN-inducible enzyme activities, including double-stranded RNA-dependent eIF2 kinase and 2',5'-oligoadenylate synthetase, are normal in IRB cells. The finding that the induction of multiple growth-related genes by several independent growth factors is inhibited in these IFN-resistant cells suggests that there is a second messenger common to both growth factor and IFN signaling pathways and that this messenger is defective in these cells.

scholarly journals AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor

2000 ◽  
Vol 20 (14) ◽  
pp. 5041-5047 ◽  
Author(s):  
Jaime Font de Mora ◽  
Myles Brown
Keyword(s):  
Estrogen Receptor ◽  
Growth Factors ◽  
Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Mapk Activation ◽  
Mitogen Activated Protein

ABSTRACT Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

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