Role of Src Signal Transduction Pathways in Scatter Factor-mediated Cellular Protection

Fan, Saijun; Meng, Qinghui; Laterra, John; Rosen, Eliot M.

doi:10.1074/jbc.m807497200

Cited by 26 publications

(21 citation statements)

References 53 publications

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“…These diverse effects of HGF are all mediated by its cell surface receptor, the transmembrane tyrosine kinase encoded by the proto-oncogene c-Met (15). The fact that HGF strongly inhibits apoptosis, partly by activating Akt via the phosphatidylinositol 3–kinase (PI3K) and Src signal transduction pathways, makes HGF an attractive target for cancer therapy (16, 17). In principle, interrupting the strong antiapoptotic effect of HGF, to which cancer cells can become addicted, can induce oncogenic shock and consequently trigger the rapid death of tumor cells (18).…”

Section: Introductionmentioning

confidence: 99%

Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

Coon

Laukert

Pedone

et al. 2010

Molecular Cancer Therapeutics

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The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh + HGF-driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing monoclonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal antibody 5E1, (d) L2G7 + cyclopamine, or (e) L2G7 + 5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response than Shh-targeted therapy. The effect of L2G7 + 5E1 combination therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7 + cyclopamine therapy was worse. The principal mechanism by which Shh-and HGF-targeted therapies inhibited tumor growth was a potent apoptotic death response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination therapy either failed to improve or even reduced survival in mice bearing Shh + HGF-induced medulloblastomas compared with monotherapy underscores the importance of preclinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active. Mol Cancer Ther; 9(9); 2627-36. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

Coon

Laukert

Pedone

et al. 2010

Molecular Cancer Therapeutics

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“…Src is both a downstream effector and activator of c-Met signaling (Herynk et al, 2007;Emaduddin et al, 2008;Fan et al, 2009;Leroy et al, 2009;Bertotti et al, 2010). Thus, our findings that Rack1, partly by inhibiting Src, promotes E-cadherin-dependent cell-cell adhesion (Figure 1b), inhibits matrigel invasion (Figures 1c and d) and regulates E-cadherin endocytosis (Figure 4), prompted us to assess Rack1's influence on HGFstimulated cell scatter and E-cadherin endocytosis.…”

Section: Rack1 Blocks Hgf-induced Cell Scatter By Inhibiting E-cadhermentioning

confidence: 99%

Rack1 promotes epithelial cell–cell adhesion by regulating E-cadherin endocytosis

Swaminathan

Cartwright

2011

Oncogene

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E-cadherin and its cytoplasmic partners, catenins, mediate epithelial cell-cell adhesion. Disruption of this adhesion allows cancer cells to invade and metastasize. Aberrant activation of the Src tyrosine kinase disrupts cell-cell contacts through an E-cadherin/catenin-dependent mechanism. Previously we showed that Rack1 regulates the growth of colon cells by suppressing Src activity at G 1 and mitotic checkpoints, and in the intrinsic apoptotic and Akt cell survival pathways. Here we show that Rack1, partly by inhibiting Src, promotes cell-cell adhesion and reduces the invasive potential of colon cancer cells. Rack1 stabilizes E-cadherin and catenins at cell-cell contacts by inhibiting the Src phosphorylation of E-cadherin, the ubiquitination of E-cadherin by the E3 ligase Hakai and the endocytosis of E-cadherin. Upon depletion and restoration of extracellular calcium, Rack1 facilitates the re-assembly of E-cadherin-containing cell-cell contacts. Rack1 also blocks HGF-induced endocytosis of E-cadherin, disruption of cell-cell contacts and cell scatter. Our results uncover a novel function of Rack1 in maintaining the junctional homeostasis of intestinal epithelial cells by regulation of the Src-and growth factor-induced endocytosis of E-cadherin.

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“…In quiescent cells, the TRAF2/TRAF3 adaptor protein complex binds to NIK and recruits NIK to cIAP1/2 ubiquitin E3 ligases, resulting in NIK ubiquitination and degradation . NIK is activated by diverse stimuli, including oxidative stress, saturated fatty acids, cytokines, endotoxins, as well as ligands that activate Toll‐like receptors (TLRs), receptor tyrosine kinases, and G‐protein‐coupled receptors . Cytokines stimulate TRAF3 degradation, leading to NIK stabilization and activation .…”

mentioning

confidence: 99%

Mouse hepatocyte overexpression of NF‐κB‐inducing kinase (NIK) triggers fatal macrophage‐dependent liver injury and fibrosis

et al. 2014

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Damaged, necrotic, or apoptotic hepatocytes release damage-associated molecular patterns that initiate sterile inflammation, and liver inflammation drives liver injury and fibrosis. Here we identified hepatic NF-κB-inducing kinase (NIK), a Ser/Thr kinase, as a novel trigger of fatal liver inflammation. NIK is activated by a broad spectrum of stimuli. It was upregulated in injured livers in both mice and humans. In primary mouse hepatocytes, NIK overexpression stimulated, independently of cell injury and death, release of numerous chemokines and cytokines that activated bone marrow-derived macrophages (BMDMs). BMDMs in turn secreted pro-apoptotic molecules that stimulated hepatocyte apoptosis. Hepatocyte-specific expression of the NIK transgene triggered massive liver inflammation, oxidative stress, hepatocyte apoptosis, and liver fibrosis, leading to weight loss, hypoglycemia, and death. Depletion of Kupffer cells/macrophages reversed NIK-induced liver destruction and death. Conclusion the hepatocyte NIK-liver immune cell axis promotes liver inflammation, injury and fibrosis, thus driving liver disease progression.

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Role of Src Signal Transduction Pathways in Scatter Factor-mediated Cellular Protection

Cited by 26 publications

References 53 publications

Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

Rack1 promotes epithelial cell–cell adhesion by regulating E-cadherin endocytosis

Mouse hepatocyte overexpression of NF‐κB‐inducing kinase (NIK) triggers fatal macrophage‐dependent liver injury and fibrosis

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