Critical Signals in Neurofibromatosis

Abstract

Loss of function of the NF1 tumor suppressor protein causes tumor formation in humans with neurofibromatosis type 1. The NF1 protein is a guanosine triphosphatase-activating protein (GAP) for Ras, which negatively regulates Ras signaling. However, the critical downstream targets of Ras that account for the disease phenotype have not been defined. One target of Ras signaling is phosphoinositide 3-kinase (PI3K). PI3K is a key regulator of signaling through the serine-threonine kinase TOR (target of rapamycin), which controls cell growth and proliferation. Johannessen et al. report that mouse embryo fibroblasts lacking NF1 show increased signaling through TOR. This activation of TOR appeared to require Ras because expression of the catalytic GAP-related domain decreased TOR signaling. In wild-type cells, Ras was necessary for activation of TOR in response to L-α-lysophosphatidic acid (a major growth factor in serum) or insulin but not for activation in response to platelet-derived growth factor. Blockade of TOR activity with its inhibitor rapamycin suppressed proliferation of human tumor cells from patients with neurofibromatosis. Thus rapamycin, already a proposed therapeutic for other forms of cancer, may be particularly effective in the treatment of neurofibromatosis type 1. C. M. Johannessen, E. E. Reczek, M. F. James, H. Brems, E. Legius, K. Cichowski, The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. U.S.A. 102 , 8573-8578 (2005). [Abstract] [Full Text]