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Identification of a novel ligand-receptor pair constitutively activated by ras oncogenes
1Vanderbilt-Ingram Cancer Center, Department of Cell Biology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
Abstract:
The Ras signaling pathway is thought to control the expression of a subset of yet to be defined genes that are crucial for cell growth and differentiation. Here we have identified by differential display a novel oncogenic Ras target, mob-5, encoding a 23-kDa cytokine-like secreted protein. Mob-5 expression could be induced by oncogenic Ha-ras and Ki-ras, but not by normal ras activation. Inhibitors of both Ha-Ras and mitogen-activated protein kinase kinase completely abolished the mob-5 expression in ras transformed cells, with concomitant loss of the transformation phenotype. Using an alkaline phosphatase-tagged Mob-5 as ligand, a putative Mob-5 receptor was identified on the cell surface of oncogenic ras transformed cells. Thus, the Mob-5/Mob-5 receptor may represent a novel putative autocrine loop coordinately activated by ras oncogenes.
Insights
Researchers discovered mob-5, a novel oncogenic Ras target gene crucial for cell growth. This gene, mob-5, may form an autocrine loop with its receptor, activated by Ras oncogenes, impacting cell transformation.
Area of Science:
- Molecular Biology
- Cellular Biology
- Oncology
Background:
- The Ras signaling pathway regulates critical cellular processes like growth and differentiation.
- Specific genes controlled by Ras, particularly in oncogenic contexts, remain largely undefined.
Purpose of the Study:
- To identify novel genes regulated by oncogenic Ras.
- To investigate the role of these genes in cancer cell transformation.
Main Methods:
- Differential display technique to identify novel gene expression.
- Utilizing oncogenic Ras (Ha-ras, Ki-ras) and normal Ras activation models.
- Employing Ras and mitogen-activated protein kinase kinase inhibitors.
- Developing an alkaline phosphatase-tagged Mob-5 ligand to identify its receptor.
Main Results:
- Identified and characterized mob-5, a novel oncogenic Ras target gene.
- Mob-5 encodes a 23-kDa cytokine-like secreted protein.
- Mob-5 expression is induced by oncogenic Ha-ras and Ki-ras, but not normal Ras.
- Ras and MAPK pathway inhibitors abolished mob-5 expression and reversed transformation phenotype.
- A putative Mob-5 receptor was identified on the cell surface of oncogenic Ras-transformed cells.
Conclusions:
- Mob-5 is a novel oncogenic Ras target gene.
- The Mob-5/Mob-5 receptor axis may constitute a new autocrine loop activated by Ras oncogenes.
- This pathway could be a potential therapeutic target in Ras-driven cancers.