Abstract
Transforming growth factor-alpha (TGF-alpha) and related proteins represent a family of transmembrane growth factors with representatives in flies and worms. Little is known about the transport of TGF-alpha and other transmembrane growth factors to the cell surface and its regulation. p59 was purified as a cytoplasmic protein, which at endogenous levels associates with transmembrane TGF-alpha. cDNA cloning of p59 revealed a 452 amino acid sequence with two PDZ domains. p59 is myristoylated and palmitoylated, and associates with the Golgi system, where it co-localizes with TGF-alpha. Its first PDZ domain interacts with the C-terminus of transmembrane TGF-alpha and select transmembrane proteins. p59 is the human homolog of GRASP55, which is structurally related to GRASP65. GRASP55 and GRASP65 have been shown to play a role in stacking of the Golgi cisternae in vitro. C-terminal mutations of transmembrane TGF-alpha, which decrease or abolish the interaction with p59, also strongly impair cell surface expression of TGF-alpha. Our observations suggest a role for membrane tethering of p59/GRASP55 to select transmembrane proteins, including TGF-alpha, in maturation and transport to the cell surface.