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Neurofibromin is a novel regulator of RAS-induced signals in primary vascular smooth muscle cells.

Abstract
Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the NF1 tumor suppressor gene. Neurofibromin is encoded by NF1 and functions as a negative regulator of Ras activity. NF1 patients develop renal artery stenosis and arterial occlusions resulting in cerebral and visceral infarcts. Further, NF1 patients develop vascular neurofibromas where tumor vessels are invested in a dense pericyte sheath. Although it is well established that aberrations in Ras signaling lead to human malignancies, emerging data generated in genetically engineered mouse models now implicate perturbations in the Ras signaling axis in vascular smooth muscular cells (VSMCs) as central to the initiation and progression of neointimal hyperplasia and arterial stenosis. Despite these observations, the function of neurofibromin in regulating VSMC function and how Ras signals are terminated in VSMCs is virtually unknown. Utilizing VSMCs harvested from Nf1+/- mice and primary human neurofibromin-deficient VSMCs, we identify a discrete Ras effector pathway, which is tightly regulated by neurofibromin to limit VSMC proliferation and migration. Thus, these studies identify neurofibromin as a novel regulator of Ras activity in VSMCs and provide a framework for understanding cardiovascular disease in NF1 patients and a mechanism by which Ras signals are attenuated for maintaining VSMC homeostasis in blood vessel walls.
AuthorsFang Li, Amy M Munchhof, Hilary A White, Laura E Mead, Theresa R Krier, Amy Fenoglio, Shi Chen, Xiaohua Wu, Shanbao Cai, Feng-Chun Yang, David A Ingram
JournalHuman molecular genetics (Hum Mol Genet) Vol. 15 Issue 11 Pg. 1921-30 (Jun 01 2006) ISSN: 0964-6906 [Print] England
PMID16644864 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Neurofibromin 1
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Becaplermin
  • ras Proteins
Topics
  • Animals
  • Becaplermin
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular (cytology)
  • Myocytes, Smooth Muscle (cytology)
  • Neurofibromin 1 (metabolism, physiology)
  • Platelet-Derived Growth Factor (metabolism)
  • Proto-Oncogene Proteins c-sis
  • ras Proteins (metabolism)

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