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Human Molecular Genetics Advance Access published online on April 27, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl114
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received March 6, 2006
Revised April 21, 2006
Accepted April 21, 2006

Article

Neurofibromin is a Novel Regulator of Ras Induced Signals in Primary Vascular Smooth Muscle Cells

Fang Li 1, Amy M. Munchhof 2, Hilary A. White 1, Laura E. Mead 1, Theresa R. Krier 1, Amy Fenoglio 1, Shi Chen 1, Xiaohua Wu 1, Shanbao Cai 1, Feng-Chun Yang 1, and David A. Ingram 3 *

1 Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202
2 Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
3 Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut St R4/470, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202

* To whom correspondence should be addressed.
David A. Ingram, E-mail: dingram{at}iupui.edu


  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. While 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.


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