title: Cation diffusion facilitator proteins modulate Raf-1 activity.
abstract: The Ras-extracellular signal-regulated kinase (ERK) cascade is a critical intracellular signaling pathway that regulates growth, survival, and differentiation. Previous work established that Ras-GTP binds to, and facilitates the activation of, the protein kinase Raf-1. Recently, it was demonstrated that the cation diffusion facilitator (CDF) proteins are involved in Ras-ERK signaling by use of a Caenorhabditis elegans genetic screen that identified suppressors of activated Ras. In the current work, we demonstrate that CDF proteins may function downstream of Ras, but upstream of Raf-1 in Xenopus oocytes. We also show that the C. elegans protein CDF-1 and its mammalian homologue ZnT-1 bind to the amino-terminal regulatory portion of Raf-1 and promote the biological and enzymatic activity of Raf-1. Furthermore, we show that Zn(2+) inhibits Raf-1 binding to ZnT-1. We propose a model in which CDF protein binding facilitates Raf-1 activation.
authors.affiliation: Center for Cardiovascular Research, the Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Tanawat
authors.initials: T
authors.lastname: Jirakulaporn
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
mesh_terms: D048948:14-3-3 Proteins; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008540:Meiosis / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014981:Xenopus; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D029742:Caenorhabditis elegans Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; C456542:cdf-1 protein, C elegans; C106207:par-5 protein, C elegans; D014446:Tyrosine 3-Monooxygenase; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins; D015032:Zinc