NF1. A segment comprising ca. 10% of the whole protein represents the only known functional module of neurofibromin. It functions as a negative regulator of Ras, another protein that is intimately involved in the regulation of cell growth and differentiation. The physiological importance of this is underscored by the observation that Ras carries characteristic mutations in 30% of all cancer tumors.

Ras can be thought of as a binary signal switch cycling between ON and OFF states which are characterized in terms of a small molecule, a guanine nucleotide, bound to the protein. In the resting cell, Ras is tightly bound to guanosine diphosphate (GDP), which is exchanged for guanosine triphosphate (GTP) upon binding of extracellular stimuli to cell membrane receptors. In the GTP-bound form, Ras interacts specifically with so-called effector proteins, thereby initiating cascades of protein-protein interactions that may finally lead to cell proliferation. To return to the inactive OFF state, Ras cleaves off the terminal phosphate moiety, the g -phosphate, of GTP in an enzymatic process, the intrinsic GTPase reaction. The remaining GDP-bound Ras is no longer able to interact with effectors, it is switched OFF. The process of GTP cleavage is very slow: Ras splits one GTP every 30 minutes. But upon interaction with neurofibromin, the rate is enhanced 100,000 fold: the underlying process is termed GTPase activation, making neurofibromin a GTPase activating protein (GAP). A common feature of the Ras mutations found in tumors is the inability of the resulting Ras proteins to cleave GTP efficiently, i.e. to turn off the switch; in addition they are not sensitive to GTPase activation by neurofibromin. Thus, understanding neurofibromin function also means understanding aspects of Ras function, linking NF1 to ca
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Contact: Klaus Scheffzek
Klaus.Scheffzek@mpi-dortmund.mpg.de
Fax: 49-231-1206-23
Max-Planck-Gesellschaft
14-Aug-1998


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