Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation.
We have reported on Spred-1 and Spred-2, which inhibit MAP kinase activation by interacting with c-kit and ras/raf. Here, we report the cloning of a third member in this family, Spred-3. Spred-3 is expressed exclusively in the brain and its gene locates in chromosome 19q13.13 in human. Like Spred-1 and -2, Spred-3 contains an EVH1 domain in the N-terminus and a Sprouty-related cysteine-rich region (SPR domain) in the C-terminus that is necessary for membrane localization. However, Spred-3 does not possess a functional c-kit binding domain (KBD), since the critical amino acid Arg residue in this region was replaced with Gly in Spred-3. Although Spred-3 suppressed growth factor-induced MAP kinase (Erk) activation, inhibitory activity of Spred-3 was lower than that of Spred-1 or Spred-2. By the analysis of chimeric molecules between Spred-3 and Spred-1, we found that the SPR domain, rather than KBD, is responsible for efficient Erk suppression. The finding of Spred-3 revealed the presence of a novel family of regulators for the Ras/MAP kinase pathway, each member of which may have different specificities for extracellular signals.
Kato
Reiko
R
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nonami
Atsushi
A
Taketomi
Takaharu
T
Wakioka
Toru
T
Kuroiwa
Asato
A
Matsuda
Yoichi
Y
Yoshimura
Akihiko
A
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002888:Chromosomes, Human, Pair 19; D003001:Cloning, Molecular; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism
D020033:Protein Isoforms; D012097:Repressor Proteins; C473798:Spred-3 protein, mouse; D014443:Tyrosine; D019009:Proto-Oncogene Proteins c-kit; D020928:Mitogen-Activated Protein Kinases