Association of the transmembrane TGF-alpha precursor with a protein kinase complex.
A variety of growth factors including transforming growth factor-alpha (TGF-alpha) are synthesized as transmembrane precursors. The short cytoplasmic domain of the transmembrane TGF-alpha precursor lacks any apparent motif associated with signal transduction. However, the sequence conservation of this cytoplasmic domain and its abundance of cysteine residues, reminiscent of the cytoplasmic domains of CD4 and CD8, suggest a biological function. In this study, we showed that transmembrane TGF-alpha was rapidly internalized after interaction with a specific antibody and that this internalization was greatly decreased when the COOH-terminal 31 amino acids were removed. Chemical cross-linking experiments revealed two associated proteins of 86 and 106 kD which coimmunoprecipitated with the TGF-alpha precursor. The association of p86 was dependent on the presence of the COOH-terminal cytoplasmic 31 amino acids of the TGF-alpha precursor, whereas p106 still remained associated when this segment was deleted. In addition, p106 was tyrosine-phosphorylated and exposed on the cell surface. The protein complex associated with transmembrane TGF-alpha displayed kinase activities towards tyrosine, serine, and threonine residues. These activities were not associated with transmembrane TGF-alpha when the COOH-terminal segment was truncated. The association of a protein kinase complex with transmembrane TGF-alpha may provide the basic elements for a "reverse" mode of signaling through the cytoplasmic domain of this growth factor, which may lead to two-directional communication during ligand-receptor interaction.
Shum
L
L
Department of Growth and Development, Anatomy, University of California at San Francisco 94143-0640.
Reeves
S A
SA
Kuo
A C
AC
Fromer
E S
ES
Derynck
R
R
D000818:Animals; D016466:CHO Cells; D017124:Conserved Sequence; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006133:Growth Substances / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
D006133:Growth Substances; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011498:Protein Precursors; D016211:Transforming Growth Factor alpha; C052268:protransforming growth factor alpha; D011494:Protein Kinases