Neurofibromatis type I is a prevalent familial cancer syndrome affecting 1 in 3500 individuals worldwide. Loss-of-function mutations in NF1 tumor suppressor gene underlie the disease. The NF1-encoded protein, neurofibromin, has been shown to function as a Ras-GTPase activating protein (GAP); however, little is known about how its activity is normally regulated or its precise role in controlling Ras signaling pathways. We have recently identified the first mechanism known to regulate neurofibromin. We found that it is rapidly degraded by the proteasome following growth factor treatment and is subsequently re-elevated to turn off Ras. In our unpublished studies we have further observed that the re-synthesized protein is phosphorylated. Because neurofibromin phosphorylation occurs precisely as Ras becomes inactivated, we hypothesize that phosphorylation may enhance neurofibromin function to acutely terminate the Ras signal. This hypothesis is supported by a variety of genetic and biochemical evidence. Our data also suggest that ERK is the regulatory kinase. Therefore, this event may represent a normal negative feedback loop that is required for proper termination of Ras signaling pathways. In the first aim we will determine the functional consequences of neurofibromin phosphorylation and firmly establish whether ERK is the regulatory kinase in vivo. In the second aim we will determine the biological significance of neurofibromin phosphorylation in a mouse model system and in cell lines expressing the phospho-mutant protein. Finally, we have also identified a novel neurofibromin interacting protein. Because it was isolated under conditions in which neurofibromin is phosphorylated, we will determine the role of phosphorylation in mediating this interaction in Aim 3. Regardless, we will molecularly dissect this interaction and test its involvement in neurofibromin function. Importantly, this avenue of investigation may enable us to identify the first new function for NF 1 in over a decade. Collectively, these aims will serve to dramatically increase our knowledge about the regulation and function of the NF1 tumor suppressor. They will also greatly contribute to our understanding of the mechanisms governing appropriate Ras attenuation and the biological importance of this fine-tuned regulation. As a result these findings may ultimately impact future therapeutic strategies for NF1 and non-NF1 related tumors.
| Liao, Sida; Maertens, Ophélia; Cichowski, Karen et al. (2018) Genetic modifiers of the BRD4-NUT dependency of NUT midline carcinoma uncovers a synergism between BETis and CDK4/6is. Genes Dev 32:1188-1200 |
| Malone, Clare F; Emerson, Chloe; Ingraham, Rachel et al. (2017) mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors. Cancer Discov 7:1450-1463 |
| Maertens, Ophélia; McCurrach, Mila E; Braun, Benjamin S et al. (2017) A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies. Cancer Res 77:5706-5711 |
| Lock, Rebecca; Ingraham, Rachel; Maertens, Ophélia et al. (2016) Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers. J Clin Invest 126:2181-90 |
| Malone, Clare F; Fromm, Jody A; Maertens, Ophélia et al. (2014) Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers. Cancer Discov 4:1062-73 |
| Hollstein, Pablo E; Cichowski, Karen (2013) Identifying the Ubiquitin Ligase complex that regulates the NF1 tumor suppressor and Ras. Cancer Discov 3:880-93 |
| McLaughlin, Sara Koenig; Olsen, Sarah Naomi; Dake, Benjamin et al. (2013) The RasGAP gene, RASAL2, is a tumor and metastasis suppressor. Cancer Cell 24:365-78 |
| Maertens, Ophélia; Johnson, Bryan; Hollstein, Pablo et al. (2013) Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov 3:338-49 |
| McGillicuddy, Lauren T; Fromm, Jody A; Hollstein, Pablo E et al. (2009) Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16:44-54 |
| Johannessen, Cory M; Johnson, Bryan W; Williams, Sybil M Genther et al. (2008) TORC1 is essential for NF1-associated malignancies. Curr Biol 18:56-62 |
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