Transmembrane TGF-alpha precursors activate EGF/TGF-alpha receptors.
TGF-alpha and EGF are structurally related factors that bind to and induce tyrosine autophosphorylation of a common receptor. Proteolytic cleavage of the transmembrane TGF-alpha precursor's external domain releases several TGF-alpha species. However, membrane-bound TGF-alpha forms remain on the surface of TGF-alpha-expressing cell lines. To evaluate the biological activity of these forms, we modified two cleavage sites in the TGF-alpha precursor coding sequence, making processing into the 50 amino acid TGF-alpha impossible. Overexpression of this cDNA in a receptor-negative cell line, partial purification, and N-terminal sequence analysis indicate the existence of two transmembrane TGF-alpha forms. These solubilized precursors induce tyrosine autophosphorylation of the EGF/TGF-alpha receptor in intact receptor-overexpressing cells, and anchorage-independent growth of NRK fibroblasts. Cell-cell contact between TGF-alpha precursor-overexpressing cells and cells expressing high numbers of receptors also resulted in receptor activation. These findings suggest a role for transmembrane TGF-alpha forms in intercellular interactions in proliferating tissues.
Brachmann
R
R
Department of Developmental Biology, Genentech, Inc., South San Francisco, California 94080.
Lindquist
P B
PB
Nagashima
M
M
Kohr
W
W
Lipari
T
T
Napier
M
M
Derynck
R
R
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D008562:Membrane Glycoproteins / Q000502:physiology*; D010766:Phosphorylation; D011498:Protein Precursors / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D013329:Structure-Activity Relationship; D015291:Transforming Growth Factors / Q000502:physiology*
D008562:Membrane Glycoproteins; D011498:Protein Precursors; D015291:Transforming Growth Factors; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases