Engineering epidermal growth factor for enhanced mitogenic potency.
Successful use of growth factors in therapeutic and bioprocessing applications requires overcoming two attenuation mechanisms: growth factor depletion and receptor down-regulation. Current ameliorative strategies use physiologically inappropriate high growth-factor concentrations, along with periodic media refeeding in vitro and reinjection or controlled-release devices in vivo. We demonstrate a new approach derived from understanding how these attenuation mechanisms arise from ligand/receptor trafficking processes. Specifically, a recombinant epidermal growth factor (EGF) mutant with reduced receptor binding affinity is a more potent mitogenic stimulus for fibroblasts than natural EGF or transforming growth factor alpha because of its altered trafficking properties.
Reddy
C C
CC
Department of Chemical Engineering, University of Illinois at Urbana-Champaign 61801, USA.
Niyogi
S K
SK
Wells
A
A
Wiley
H S
HS
Lauffenburger
D A
DA
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005818:Genetic Engineering; D051379:Mice; D008934:Mitogens / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000494:pharmacology
D008934:Mitogens; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors