The Ras pathway is a critical signal transduction cascade involved in regulating cellular proliferation, differentiation, and survival. Members of the Raf serine/threonine kinase family are key intermediates in this pathway, functioning to relay signals from activated Ras to the downstream protein kinases, MEK and ERK. Three Raf proteins are found in mammalian cells, Raf-1, A-Raf, and B-Raf. As might be expected for proteins so centrally involved in cell signaling, the Raf kinases also contribute to oncogenic transformation and cancer. For example, mutation or amplification of upstream regulators of Raf, such as receptor tyrosine kinases and Ras, frequently induces deregulated signaling through the Raf/MEK/ERK cascade in tumors harboring these alleles. Moreover, constitutively active Raf proteins can themselves cause cell transformation. In particular, mutation of the B-Raf family member is observed in 67% of malignant melanomas as well as in many colorectal, ovarian, and papillary thyroid carcinomas. During this past fiscal year, our research identified CK2 as an upstream protein kinase that contributes to Raf activation. Our studies have also revealed that the oncogenic potential of the B-Raf kinase can be altered by specific phosphorylation events and protein interactions. Together, these findings identify potential targets for therapeutic intervention in tumors with constitutive Ras- or Raf-dependent signaling.
| Ritt, Daniel A; Abreu-Blanco, María T; Bindu, Lakshman et al. (2016) Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit. Mol Cell 64:875-887 |
| Shalin, Sara C; Hernandez, Caterina M; Dougherty, Michele K et al. (2006) Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation. Neuron 50:765-79 |
| Ritt, Daniel A; Daar, Ira O; Morrison, Deborah K (2005) KSR Regulation of the Raf-MEK-ERK Cascade. Methods Enzymol 407:224-37 |
| Dougherty, Michele K; Muller, Jurgen; Ritt, Daniel A et al. (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17:215-24 |
| Weber, Hans Oliver; Ludwig, Robert L; Morrison, Deborah et al. (2005) HDM2 phosphorylation by MAPKAP kinase 2. Oncogene 24:1965-72 |
| Murakami, Monica S; Moody, Sally A; Daar, Ira O et al. (2004) Morphogenesis during Xenopus gastrulation requires Wee1-mediated inhibition of cell proliferation. Development 131:571-80 |
| Dougherty, Michele K; Morrison, Deborah K (2004) Unlocking the code of 14-3-3. J Cell Sci 117:1875-84 |
| Ory, Stephane; Morrison, Deborah K (2004) Signal transduction: implications for Ras-dependent ERK signaling. Curr Biol 14:R277-8 |
| Morrison, Deborah K (2004) Cancer: enzymes play molecular tag. Nature 428:813-5 |
| Janssen, Richard A J; Kim, Phillia N; Mier, James W et al. (2003) Overexpression of kinase suppressor of Ras upregulates the high-molecular-weight tropomyosin isoforms in ras-transformed NIH 3T3 fibroblasts. Mol Cell Biol 23:1786-97 |
Showing the most recent 10 out of 16 publications
