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 has elucidated several important mechanisms contributing to the regulation of both normal and oncogenic Raf signaling. Our studies have revealed that the KSR1 scaffold plays a critical role in modulating the intensity and duration of Raf signaling emanating from the plasma membrane in response to growth factor treatment. In addition, we have found that the KSR expression levels can alter the effects of Raf inhibitors on oncogenic Ras/ERK signaling. Specifically, KSR1 competes with C-Raf for inhibitor-induced binding to B-Raf and in doing so attenuates the paradoxical activating effect of these drugs on ERK signaling. Our studies have also revealed that the oncogenic potential of the B-Raf kinase can be altered by specific phosphorylation events (e. g., phosphorylation on inhibitory feedback sites) and protein interactions (e.g., 14-3-3 binding and heterodimerization with C-Raf). Taken together, these findings identify potential targets for therapeutic intervention in tumors with constitutive Ras- or Raf-dependent signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010329-12
Application #
8348977
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2011
Total Cost
$631,462
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Durrant, David E; Morrison, Deborah K (2018) Targeting the Raf kinases in human cancer: the Raf dimer dilemma. Br J Cancer 118:3-8
Neiswender, James V; Kortum, Robert L; Bourque, Caitlin et al. (2017) KIT Suppresses BRAFV600E-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling. Cancer Res 77:5820-5830
Holderfield, Matthew; Morrison, Deborah K (2016) RAS signaling: Divide and conquer. Nat Chem Biol 13:7-8
Ritt, Daniel A; Abreu-Blanco, MarĂ­a 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
Zhou, Bingying; Ritt, Daniel A; Morrison, Deborah K et al. (2016) Protein Kinase CK2? Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2? Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. J Biol Chem 291:17804-15
Kortum, Robert L; Morrison, Deborah K (2015) Path Forward for RAF Therapies: Inhibition of Monomers and Dimers. Cancer Cell 28:279-81
Freeman, Alyson K; Ritt, Daniel A; Morrison, Deborah K (2013) The importance of Raf dimerization in cell signaling. Small GTPases 4:
Freeman, Alyson K; Ritt, Daniel A; Morrison, Deborah K (2013) Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. Mol Cell 49:751-8
Morrison, Deborah K (2012) MAP kinase pathways. Cold Spring Harb Perspect Biol 4:
Logue, Jeremy S; Morrison, Deborah K (2012) Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Genes Dev 26:641-50

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