Activation of extracellular signal-regulated kinase 2 by a novel Abl-binding protein, ST5.
The human ST5 gene encodes three proteins with predicted molecular masses of 126, 82, and 70 kDa. These widely expressed proteins share a C-terminal region that bears significant sequence homology to a group of GDP/GTP exchange proteins for the Rab3 family of small GTP binding proteins. The N-terminal region of the largest ST5 protein, p126, contains two proline-rich sequences, PR1 and PR2, with consensus motifs similar to Src homology 3 (SH3) binding regions and to mitogen-activated protein kinase (MAPK) phosphorylation sites. Based on these properties, we sought to investigate the activity of ST5 proteins in signal transduction pathways. In vitro, p126 displayed preferential binding to c-Abl SH3, as compared with other SH3 domains. This interaction was mediated by the PR2 sequence. In vivo, expression of p126, but not p82 or p70, activated MAPK/ERK2 in response to EGF in COS-7 cells. Expression of c-Abl with p126 greatly enhanced this activity. Deletion of PR1 blocked the ability of p126 to activate ERK2. Deletion of PR2 did not affect the basal activity, but blocked the stimulatory effect of c-Abl. Whereas p82 expression had no effect on ERK2 activation by p126, p70 completely abrogated this activity. These observations suggest that ST5 can function as a signaling protein and can provide a link between c-Abl and ERK2.
Majidi
M
M
Department of Cellular Pathology, Armed Forces Institute of Pathology, Washington, D.C. 20306-6000, USA.
Hubbs
A E
AE
Lichy
J H
JH
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
C077272:DENND2B protein, human; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D016315:Proto-Oncogene Proteins c-abl; D019950:Mitogen-Activated Protein Kinase 1