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 cy toplasmic domain of the transmembrane TGF-alpha precursor lacks any ap parent motif associated with signal transduction. However, the sequenc e conservation of this cytoplasmic domain and its abundance of cystein e residues, reminiscent of the cytoplasmic domains of CD4 and CD8, sug gest a biological function. In this study, we showed that transmembran e 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 exp eriments revealed two associated proteins of 86 and 106 kD which coimm unoprecipitated with the TGF-alpha precursor. The association of p86 w as dependent on the presence of the COOH-terminal cytoplasmic 31 amino acids of the TGF-alpha precursor, whereas p106 still remained associa ted when this segment was deleted. In addition, p106 was tyrosine-phos phorylated and exposed on the cell surface. The protein complex associ ated with transmembrane TGF-alpha displayed kinase activities towards tyrosine, serine, and threonine residues. These activities were not as sociated with transmembrane TGF-alpha when the COOH-terminal segment w as truncated. The association of a protein kinase complex with transme mbrane TGF-alpha may provide the basic elements for a ''reverse'' mode of signaling through the cytoplasmic domain of this growth factor, wh ich may lead to two-directional communication during ligand-receptor i nteraction.