Integral membrane glycoprotein properties of the prohormone pro-transforming growth factor-α

Abstract

Transforming growth factor- α (TGF- α) is a mitogenically active polypeptide hormone produced by acutely proliferating neoplastic and embryonic tissues^1–4. Molecular cloning of TGF-α cDNA from human and rat has indicated that this factor is synthesized as part of a larger precursor, proTGF-α^5,6. An intriguing feature of proTGF-α is that it contains a sequence of 24 hydrophobic amino acids following the bioactive TGF-α sequence. Similar hydrophobic sequences present in transmembrane proteins are cotranslationally anchored into the phospholipid bilayer of the rough endoplasmic reticulum^7,8, suggesting the possibility that proTGF-α might be an integral membrane protein. Other secretory proteins including all known prohormones lack membrane anchoring sequences and are completely translocated across the endoplasmic reticulum membrane^7,8. To address the question of whether proTGF-α is as an integral membrane protein we have translated rat proTGF-α mRNA transcripts in the presence of rough endoplasmic reticulum membrane vesicles. The results indicate that proTGF-α is synthesized as an integral membrane glycoprotein. The 50-amino-acid TGF-α sequence in proTGF-α is exposed to the fluid extracellular phase where it can be released after cleavage by the appropriate enzyme.