Neurofibromin binds to caveolin-1 and regulates ras, FAK, and Akt.
Neurofibromin (Nf1) is an approximately 280 kDa protein having tumor suppressor function, presumably by virtue of its GTPase activating domain, but little is known regarding molecular aspects of its effector pathways. Caveolin-1 (Cav-1) regulates diverse signaling molecules and has itself been implicated as a tumor suppressor. Here we demonstrate that Nf1 binds to Cav-1's scaffolding domain and co-immunoprecipitates with Cav-1. Analysis of Nf1's primary structure reveals four potential caveolin binding domains, and interestingly, in individuals with neurofibromatosis I, missense mutations occur with high frequency in 3 of the 4 putative domains. We show that Nf1 modulates ras, Akt, and focal adhesion kinase pathways, thereby affecting cytoskeletal organization; moreover, Nf1's effects on signaling are altered when lipid rafts and caveolae are disrupted by cholesterol depletion. These novel findings provide insight into possible signaling mechanisms of Nf1 and suggest that together Nf1 and Cav-1 may coordinately regulate cell growth and differentiation.
Boyanapalli
Madanamohan
M
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Lahoud
Oscar B
OB
Messiaen
Ludwine
L
Kim
Bhumsoo
B
Anderle de Sylor
Marianna S
MS
Duckett
Sara J
SJ
Somara
Sita
S
Mikol
Daniel D
DD
D000818:Animals; D001921:Brain / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D025542:Neurofibromin 1 / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism*
D051242:Caveolin 1; D025542:Neurofibromin 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D051058:Oncogene Protein v-akt; D018631:ras Proteins