Transmembrane transforming growth factor-alpha tethers to the PDZ domain-containing, Golgi membrane-associated protein p59/GRASP55

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 transmem brane growth factors to the cell surface and its regulation. p59 was purifi ed as a cytoplasmic protein, which at endogenous levels associates with tra nsmembrane TGF-alpha. cDNA cloning of p59 revealed a 452 amino acid sequenc e with two PDZ domains. p59 is myristoylated and palmitoylated, and associa tes 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 sel ect transmembrane proteins, p59 is the human homolog of GRASP55, which is s tructurally related to GRASP65. GRASP55 and GRASP65 have been shown to play a role in stacking of the Golgi cisternae in vitro, C-terminal mutations o f transmembrane TGF-alpha, which decrease or abolish the interaction with p 59, also strongly impair cell surface expression of TGF-alpha. Our observat ions suggest a role for membrane tethering of p59/GRASP55 to select transme mbrane proteins, including TGF-alpha, in maturation and transport to the ce ll surface.