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 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.
Kuo
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Departments of Growth and Development, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, CA 94143-0640, USA.
Zhong
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Lane
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Derynck
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D006224:Cricetinae; D003593:Cytoplasm / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000378:metabolism*; D000077614:Golgi Matrix Proteins; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009227:Myristic Acids / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000502:physiology*
D018076:DNA, Complementary; C108705:GORASP1 protein, human; C122048:GORASP2 protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D009227:Myristic Acids; D010169:Palmitic Acids; D016211:Transforming Growth Factor alpha