Neurofibromatosis type 1 (NF1) gene encodes neurofibromin, a GTPase-activating protein. The tumor suppressor function of neurofibromin involves:

• A Inhibiting the PI3K-AKT pathway by dephosphorylating PIP3
• B Activating the Hippo pathway by phosphorylating YAP/TAZ
• C Stabilizing p53 by inhibiting MDM2 ubiquitin ligase activity
• D Accelerating GTP hydrolysis on RAS, converting active RAS-GTP to inactive RAS-GDP ✓

Explanation

Neurofibromin is a Ras-GTPase activating protein (Ras-GAP) that catalyzes the hydrolysis of active Ras-GTP to inactive Ras-GDP, thus negatively regulating Ras/MAPK signaling. Loss-of-function mutations in NF1 lead to constitutively active Ras, driving uncontrolled cell proliferation in neural crest-derived cells. This explains the predisposition to neurofibromas, malignant peripheral nerve sheath tumors, juvenile myelomonocytic leukemia, and other tumors. PTEN is the phosphatase that dephosphorylates PIP3 (PI3K antagonist). Hippo pathway regulation involves LATS1/2 kinases.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.