A novel mechanism regulating growth factor association with the cell surface: identification of a PDGF retention domain.
Platelet-derived growth factor (PDGF) chimeras were used to map a domain responsible for either efficient secretion of PDGF-A or the tight cell association of PDGF-B to their carboxy-terminal domains. Introduction of stop codons within PDGF-A or PDGF-B further dissected their respective carboxy-terminal domains. Although successive deletions of the PDGF-A carboxyl terminus did not impair its secretion, incremental deletions from the carboxyl terminus of PDGF-B abrogated its membrane retention properties and promoted secretion. By this approach, PDGF-B retention properties could be localized to PDGF-B residues 212-226. A processed form of PDGF-B, which contained this domain, was expressed at the cell surface but not released. Comparison of PDGF-B with PDGF-A revealed an analogous sequence located at the PDGF-A carboxyl terminus. We demonstrated that this PDGF-A domain also acts as a retention sequence under conditions that inhibit its proteolytic cleavage. Thus, differences in PDGF-A and PDGF-B secretion relate to differential proteolytic processing of analogous retention domains. All of these findings establish a new mechanism for stable growth factor presentation at the cell surface.
LaRochelle
W J
WJ
Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
May-Siroff
M
M
Robbins
K C
KC
Aaronson
S A
SA
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002678:Chimera; D006868:Hydrolysis; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010449:Peptide Mapping; D010982:Platelet-Derived Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor