title: Secretion of hepatoma-derived growth factor is regulated by N-terminal processing.
abstract: Hepatoma-derived growth factor (HDGF) was first purified as a growth factor secreted by hepatoma cells. It promotes angiogenesis and has been related to tumorigenesis. To date, little is known about the molecular mechanisms of HDGF functions and especially its routes or regulation of secretion. Here we show that secretion of HDGF requires the N-terminal 10 amino acids and that this peptide can mediate secretion of other proteins, such as enhanced green fluorescent protein, if fused to their N-terminus. Our results further demonstrate that cysteine residues at positions 12 and 108 are linked via an intramolecular disulfide bridge. Surprisingly, phosphorylation of serine 165 in the C-terminal part of HDGF plays a critical role in the secretion process. If this serine is replaced by alanine, the N-terminus is truncated, the intramolecular disulfide bridge is not formed and the protein is not secreted. In summary, these observations provide a model of how phosphorylation, a disulfide bridge and proteolytic cleavage are involved in HDGF secretion.
authors.affiliation: Center for Biomolecular Interactions Bremen, Department of Biochemistry, University of Bremen, Germany.
authors.forename: Ketan
authors.initials: K
authors.lastname: Thakar
authors.forename: Tim
authors.initials: T
authors.lastname: Kröcher
authors.forename: Soniya
authors.initials: S
authors.lastname: Savant
authors.forename: Doron
authors.initials: D
authors.lastname: Gollnast
authors.forename: Sørge
authors.initials: S
authors.lastname: Kelm
authors.forename: Frank
authors.initials: F
authors.lastname: Dietz
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D014162:Transfection
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C485184:enhanced green fluorescent protein; C051610:hepatoma-derived growth factor; D049452:Green Fluorescent Proteins; D003545:Cysteine