Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation

C-Met, the receptor of hepatocyte growth factor (HGF), through overexpression or mutation, is a major protooncogene that provides an attractive molecular target for cancer therapy. HGF/c-Met–induced tumorigenesis is dependent, in part, on the transcription factor and oncogene signal transducer and activator of transcription 3 (STAT3), which is believed to be activated by the receptor at the plasma membrane and then to travel to the nucleus where it acts. We demonstrate that although the robust signal to STAT3 elicited from the cytokine oncostatin-M does indeed support this mechanism of STAT3 action, for the weaker STAT3 signal emanating from c-Met, the activated receptor itself needs to be delivered to a perinuclear endosomal compartment to sustain phosphorylated STAT3 in the nucleus. This is signal specific because c-Met–induced extracellular signal-regulated kinase nuclear accumulation does not require receptor trafficking to the perinuclear compartment. This response is triggered from peripheral endosomes. Thus, control of growth factor receptor traffic determines the nature of the signal output, providing novel opportunities for intervention

The Role of PI3K in Met Driven Cancer: A Recap

The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. However RTK inhibitors can lead to drug resistance, explaining the necessity to develop therapies that target downstream signaling. Phosphatidylinositide 3-kinase (PI3K) is one of the most deregulated pathways in cancer and implicated in various types of cancer. PI3K signaling is also a major signaling pathway downstream of RTK, including Met. PI3K major effectors include Akt and “mechanistic Target of Rapamycin” (mTOR), which each play key roles in numerous and various cell functions. Advancements made due to the development of molecular and pharmaceutical tools now allow us to delve into the roles of each independently. In this review, we summarize the current understanding we possess of the activation and role of PI3K/Akt/mTOR, downstream of Met, in cancer

The Role of PI3K in Met Driven Cancer: A Recap

The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. However RTK inhibitors can lead to drug resistance, explaining the necessity to develop therapies that target downstream signaling. Phosphatidylinositide 3-kinase (PI3K) is one of the most deregulated pathways in cancer and implicated in various types of cancer. PI3K signaling is also a major signaling pathway downstream of RTK, including Met. PI3K major effectors include Akt and "mechanistic Target of Rapamycin" (mTOR), which each play key roles in numerous and various cell functions. Advancements made due to the development of molecular and pharmaceutical tools now allow us to delve into the roles of each independently. In this review, we summarize the current understanding we possess of the activation and role of PI3K/Akt/mTOR, downstream of Met, in cancer

(A) HeLa cells stimulated with HGF for 0 or 120 min alone or in the presence of 1 μM Gö6976 or 1 μM vinblastine were stained for STAT3 and c-Met

Confocal sections are shown. Bars, 20 μm. (B and C) Quantitation of STAT3 nuclear-cytoplasmic ratios (STAT3 N/C ratio). ***, P < 0.0001. (D) Quantitation of STAT3 nuclear-cytoplasmic ratios under oncostatin M stimulation for 0 and 120 min in presence of 1 μM vinblastine. ***, P < 0.0001 (pictures not shown). (E) Cells were transfected with myc-dynamitin and stained with STAT3, Myc, and DAPI after 120 min of stimulation with HGF. The plot represents the quantitation of STAT3 nuclear-cytoplasmic ratios in nontransfected and transfected cells. ***, P < 0.0001 (Fig. S2 E [pictures], available at ). (F) Confocal projections of PKCα knockout or wild-type mouse embryo fibroblasts, stained for STAT3 and DAPI. Bars, 20 μm. (G) Quantitation of ERK1/2 nuclear-cytoplasmic ratios in cells stimulated with HGF for 0 or 120 min in the absence or presence of 1 μM vinblastine. (H) Confocal section of ERK1/2 nuclear localization and endosomal c-Met in cells stimulated with HGF and vinblastine for 120 min. Bar, 20 μm. (I) Cells were stimulated with HGF for 0, 30, or 120 min in the absence or presence of 1 μM vinblastine. Western blots for phosphorylated STAT3 (Y705), tubulin, and phosphorylated ERK1/2. Molecular masses are shown in kD. (J) Densitometric analysis of I. The bars represent fold increase of P-STAT3/tubulin and P-ERK/tubulin ratios between HGF for 120 and 0 min obtained by densitometry in three independent experiments. Error bars represent SEM.<p><b>Copyright information:</b></p><p>Taken from "Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation"</p><p></p><p>The Journal of Cell Biology 2008;182(5):855-863.</p><p>Published online 8 Sep 2008</p><p>PMCID:PMC2528569.</p><p></p

In A and B, HeLa cells transfected with control or CHC RNAi were treated by HGF for 0 or 120 min

(A) Confocal projections of cells stained for STAT3 and DAPI. Bars, 20 μm. (B) Quantitation of STAT3 nuclear-cytoplasmic ratios (STAT3 N/C ratio). ***, P < 0.0001. (C) Cells incubated in 80 μM dynasore were not stimulated or stimulated with HGF for 120 min or oncostatin M for 30 min. Confocal sections of cells stained for STAT3 and DAPI. Bars, 20 μm. (D) Quantitation of STAT3 nuclear-cytoplasmic ratios. (E) Confocal projections of five Z sections of cells transfected (T) or not (NT) with myc-AP180C and stained with STAT3, Myc, and DAPI after 120 min of stimulation with HGF or oncostatin M. Bars, 20 μm. (F) Quantitation of STAT3 nuclear intensity in Myc-AP180C T versus NT. The graphs show the nuclear STAT3 accumulation expressed as a ratio (T/NT) for myc-AP180C transfected versus nontransfected cells. The columns are mean values and the error bars are SD. An unpaired test was performed. *, P < 0.01. (G) Cells were stimulated with HGF for 0 and 120 min in the absence or presence of 80 μM dynasore. Confocal sections of cells stained for ERK1/2 and DAPI are shown. Bars, 20 μm. (H) Quantitation of ERK1/2 nuclear-cytoplasmic ratios. ***, P < 0.0001. (I and J). Cells were treated by HGF for 0 or 120 min. Western blots for CHC, phosphorylated STAT3 (Y705), pan-STAT3, phosphorylated c-Met (tyrosine 1349), pan–c-Met and phosphorylated ERK1/2. The numbers represent fold increase of P-STAT3/STAT3 or P-STAT3/tubulin and P-ERK/tubulin ratios between HGF for 120 and 0 min obtained by densitometry in three independent experiments. (I) Cells were transfected with control or CHC RNAi. (J) Cells were treated or not by 80 μM dynasore. Molecular masses are shown in kD.<p><b>Copyright information:</b></p><p>Taken from "Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation"</p><p></p><p>The Journal of Cell Biology 2008;182(5):855-863.</p><p>Published online 8 Sep 2008</p><p>PMCID:PMC2528569.</p><p></p

La Santé publique et le nucléaire

Lebullenger Joël, Diverres Arnaud, Freytos Hélène, Garnier Christophe, Kermorgant Gaëlle, Leberre Stéphanie, Mancel Carole, Mauguet Nadine, Pasquini Annalisa. La Santé publique et le nucléaire. In: Revue juridique de l'Ouest, N° Spécial 1996. La santé. pp. 187-209