Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor.
Mutations in the NF1 tumor suppressor underlie the familial tumor predisposition syndrome neurofibromatosis type I. Although its encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (GAP), nothing is known about how it is normally regulated or its precise role in controlling Ras signaling pathways. We show here that neurofibromin is dynamically regulated by the ubiquitin-proteasome pathway. Degradation is rapidly triggered in response to a variety of growth factors and requires sequences adjacent to the catalytic GAP-related domain of neurofibromin. However, whereas degradation is rapid, neurofibromin levels are re-elevated shortly after growth factor treatment. Accordingly, Nf1-deficient mouse embryonic fibroblasts (MEFs) exhibit an enhanced activation of Ras, prolonged Ras and ERK activities, and proliferate in response to subthreshold levels of growth factors. Thus, the dynamic proteasomal regulation of neurofibromin represents an important mechanism of controlling both the amplitude and duration of Ras-mediated signaling. Furthermore, this previously unrecognized Ras regulatory mechanism may be exploited therapeutically.
Cichowski
Karen
K
Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. kcichowski@rics.bwh.harvard.edu
Santiago
Sabrina
S
Jardim
Melanie
M
Johnson
Bryan W
BW
Jacks
Tyler
T
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D025542:Neurofibromin 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D020729:p120 GTPase Activating Protein / Q000187:drug effects / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D025542:Neurofibromin 1; D010982:Platelet-Derived Growth Factor; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D020729:p120 GTPase Activating Protein; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins