A 32-year-old woman with café-au-lait spots, axillary freckling, and multiple cutaneous neurofibromas is found to carry a germline NF1 mutation. The protein neurofibromin encoded by NF1 functions as a:

• A GTPase-activating protein (GAP) that accelerates intrinsic GTP hydrolysis by RAS, maintaining it in the inactive GDP-bound state ✓
• B Guanine nucleotide exchange factor (GEF) that loads GTP onto RAS to activate downstream MAPK signaling
• C Direct inhibitor of cyclin-dependent kinase 4 that prevents G1/S transition
• D E3 ubiquitin ligase that tags activated EGFR for lysosomal degradation

Explanation

Neurofibromin contains a RAS-GAP (GTPase activating protein) domain that binds active RAS-GTP and dramatically accelerates its intrinsic GTPase activity, hydrolyzing GTP to GDP and returning RAS to its inactive state. When NF1 is lost, RAS remains constitutively active in the GTP-bound state, driving continuous MAPK and PI3K/AKT signaling and promoting cell proliferation. GEFs (e.g., SOS) perform the opposite function — loading GTP onto RAS. This explains why NF1 is a tumor suppressor whose loss phenocopies, in part, an activating RAS mutation.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.