Related Experiment Video
Updated: Jul 17, 2026
05:18
Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells
Published on: June 9, 2020
Ras effector pathways modulate scatter factor-stimulated NF-kappaB signaling and protection against DNA damage.
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057-1469, USA.
Oncogene
|February 14, 2007
Summary
Ras proteins enhance scatter factor (SF) protection of tumor cells by activating nuclear factor-kappa B (NF-kappaB) signaling. These pathways modulate SF-mediated cell survival at the IKK complex.
Area of Science:
- Cellular biology
- Molecular oncology
- Signal transduction
Background:
- Scatter factor (SF), also known as hepatocyte growth factor, accumulates in tumors and protects cancer cells from DNA-damaging agents.
- SF-mediated cell protection involves a signaling cascade including c-Met, PI3 kinase, c-Akt, Pak1, and NF-kappaB.
Purpose of the Study:
- To investigate the role of Ras proteins in SF-mediated NF-kappaB activation and cell protection.
- To elucidate the specific pathways downstream of Ras involved in this process.
Main Methods:
- Utilized DU-145 and MDCK cells treated with adriamycin, a topoisomerase IIalpha inhibitor.
- Employed Ras effector loop mutants and studied downstream effectors like PI3 kinase, Raf1, MEK3/6, p38, RalA, and IKK-beta.
Main Results:
- Ras proteins (H-Ras and R-Ras) enhance SF-mediated NF-kappaB activation and cell protection against adriamycin.
- Ras/PI3 kinase and Ras/Raf1 pathways contribute to SF-induced NF-kappaB signaling.
- Raf1 positively regulates SF-mediated NF-kappaB activity and cell protection, independent of the classical Raf1 --> MEK1/2 --> ERK1/2 pathway.
- A MEK3/6 --> p38 pathway is involved in SF-mediated NF-kappaB activation.
- RalA negatively regulates SF-mediated NF-kappaB activity and cell protection.
- Ras, Raf1, and RalA modulate SF-stimulated NF-kappaB activity by regulating IKK-beta kinase activity.
Conclusions:
- Ras proteins, through distinct downstream pathways including Raf1 and RalA, converge to modulate NF-kappaB activation.
- These pathways interact with the IKK complex to regulate SF-mediated survival signaling in tumor cells.
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:19Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:07MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
02:26NF-kB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
01:17The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...