A-Raf associates with and regulates platelet-derived growth factor receptor signalling

Mahon, Elizabeth S.; Hawrysh, Andrea D.; Chagpar, Ryaz; Johnson, Lindsey M.; Anderson, Deborah H.

doi:10.1016/j.cellsig.2004.11.006

Cited by 19 publications

(11 citation statements)

References 76 publications

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“…During development, A-Raf transduces signals initiated by a variety of mitogens and growth factors, especially in the urogenital and gastrointestinal tracts (Mahon et al, 2005). As shown in Figure 2, active A-Raf induces the activation of the MEK/ERK pathway, although its affinity for MEK proteins is significantly lower than that of other Raf kinases (Marais et al, 1997).…”

Section: (Omim#*311010)mentioning

confidence: 99%

MAP3Ks as central regulators of cell fate during development

Craig

Stevens

Vaillancourt

et al. 2008

Developmental Dynamics

112

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Section: (Omim#*311010)mentioning

confidence: 99%

MAP3Ks as central regulators of cell fate during development

Craig

Stevens

Vaillancourt

et al. 2008

Developmental Dynamics

112

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“…Several studies have provided evidence for Ras isoform-specific signaling that is regulated by different intracellular compartments and coupling proteins (34,46,47). In HeLa cells, treatment with a Ras inhibitor augmented autophagy independent of the classical Ras/ C-Raf pathway (48).…”

Section: +mentioning

confidence: 99%

Activation of Cytosolic Phospholipase A2α by Epidermal Growth Factor (EGF) and Phorbol Ester in HeLa Cells: Different Effects of Inhibitors for EGF Receptor, Protein Kinase C, Src, and C-Raf

et al. 2009

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Abstract. In several types of cancer cells, prostaglandins produced via the over-expression of epidermal growth factor receptor (EGFR) and cyclooxygenases regulate cell growth. We investigated the signaling mechanisms for the release of arachidonic acid (AA, a precursor for prostaglandins) in human cervical carcinoma HeLa cells. Treatment with EGF and 4β-phorbol 12-myristate 13-acetate (PMA) with A23187 released AA accompanied by the phosphorylation of extracellular signal-regulated kinases (ERK1/2). Pharmacological experiments showed that the responses (ERK phosphorylation and AA release) induced by EGF and PMA were mediated by a mitogen-activated protein kinase /ERK kinase (MEK) -ERK -α-type cytosolic phospholipase A 2 (cPLA 2 α) pathway and that EGFR couples with the pathway in a manner insensitive to sorafenib, an inhibitor of B-and C-Raf, enzymes upstream of MEK. Activation of protein kinase C by PMA couples with the pathway partly in a sorafenib-sensitive and probably C-Raf-mediated manner and partly in a family of Src tyrosine kinases (Src)-dependent and sorafenib-insensitive manner. Co-treatment with sorafenib and an inhibitor of Src family members additionally inhibited the PMA-induced release of AA. Cross-talk between EGFR and protein kinase C was not observed. In human lung carcinoma A549 cells, the release of AA by EGF was insensitive to sorafenib. Possible mechanisms for the sorafenib-insensitive activation of the MEK-ERK-cPLA 2 α pathway are discussed.

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“…Further animal work has suggested that p85 may be able to modulate the tumorigenicity of PTEN( +/− ) mice (9), as well as the observed insulin sensitivity (10) via effects on PTEN. Our previous work suggested p85α may bind a negative regulator of PI3K activity (11). Therefore, we set out to determine if p85 could bind to and directly regulate PTEN.…”

mentioning

confidence: 99%

Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase

Chagpar

Links²,

Pastor³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

181

189

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The phosphatidylinositol 3-kinase (PI3K) signaling pathway is deregulated in many human diseases including cancer, diabetes, obesity, and autoimmunity. PI3K consists of a p110 catalytic protein and a p85α regulatory protein, required for the stabilization and localization of p110-PI3K activity. The p110-PI3K enzyme generates the key signaling lipid phosphatidylinositol 3,4,5-trisphosphate, which is dephosphorylated by the PI3-phosphatase PTEN. Here we show another function for the p85α regulatory protein: it binds directly to and enhances PTEN lipid phosphatase activity. We demonstrate that ectopically expressed FLAG-tagged p85 coimmunoprecipitates endogenous PTEN in an epidermal growth factor dependent manner. We also show epidermal growth factor dependent coimmunoprecipitation of endogenous p85 and PTEN proteins in HeLa cells. Thus p85 regulates both p110-PI3K and PTEN-phosphatase enzymes through direct interaction. This finding underscores the need for caution in analyzing PI3K activity because anti-p85 immunoprecipitations may contain both p85:p110-PI3K and p85:PTEN-phosphatase enzymes and thus measure net PI3K activity. We identify the N-terminal SH3-BH region of p85α, absent in the smaller p55α and p50α isoforms, as the region that mediates PTEN binding and regulation. Cellular expression of p85ΔSH3-BH results in substantially increased magnitude and duration of pAkt levels in response to growth factor stimulation. The ability of p85 to bind and directly regulate both p110-PI3K and PTEN-PI3-phosphatase allows us to explain the paradoxical insulin signaling phenotypes observed in mice with reduced PI3K or PTEN proteins. This discovery will impact ongoing studies using therapeutics targeting the PI3K/PTEN/Akt pathway.

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A-Raf associates with and regulates platelet-derived growth factor receptor signalling

Cited by 19 publications

References 76 publications

MAP3Ks as central regulators of cell fate during development

MAP3Ks as central regulators of cell fate during development

Activation of Cytosolic Phospholipase A2α by Epidermal Growth Factor (EGF) and Phorbol Ester in HeLa Cells: Different Effects of Inhibitors for EGF Receptor, Protein Kinase C, Src, and C-Raf

Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase

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