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Department of Medicine, University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599
Insulin-like growth factor-binding protein-5 (IGFBP-5) has been
shown to bind to fibroblast extracellular matrix (ECM). Extracellular matrix binding of IGFBP-5 leads to a decrease in its affinity for
insulin-like growth factor-I (IGF-I), which allows IGF-I to better
equilibrate with IGF receptors. When the amount of IGFBP-5 that is
bound to ECM is increased by exogenous addition, IGF-I's effect on
fibroblast growth is enhanced. In this study we identified the specific
basic residues in IGFBP-5 that mediate its binding to porcine
smooth-muscle cell (pSMC) ECM. An IGFBP-5 mutant containing alterations
of basic residues at positions 211, 214, 217, and 218 had the greatest
reduction in ECM binding, although three other mutants, R214A,
R207A/K211N, and K202A/R206N/R207A, also had major decreases. In
contrast, three other mutants, R201A/K202N/R206N/R208A, and K217N/R218A
and K211N, had only minimal reductions in ECM binding. This suggested
that residues R207 and R214 were the most important for binding,
whereas alterations in K211 and R218, which align near them, had
minimal effects. To determine the effect of a reduction in ECM binding
on the cellular replication response to IGF-I, pSMCs were transfected
with the mutant cDNAs that encoded the forms of IGFBPs with the
greatest changes in ECM binding. The ECM content of IGFBP-5 from
cultures expressing the K211N, R214A, R217A/R218A, and
K202A/R206N/R207A mutants was reduced by 79.6 and 71.7%, respectively,
compared with cells expressing the wild-type protein. In contrast,
abundance of the R201A/K202N/R206N/R208A mutant was reduced by only
14%. Cells expressing the two mutants with reduced ECM binding had
decreased DNA synthesis responses to IGF-I, but the cells expressing
the R201A/K202N/R206N/R208A mutant responded well to IGF-I. The
findings suggest that specific basic amino acids at positions 207 and
214 mediate the binding of IGFBP-5 to pSMC/ECM. Smooth-muscle cells
that constitutively express the mutants that bind weakly to ECM are
less responsive to IGF-I, suggesting that ECM binding of IGFBP-5 is an
important variable that determines cellular responsiveness.
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