The proliferative action of
insulin-like growth factors (
IGF-I and -II) is mediated via the type I IGF receptor (IGF-IR) and is modulated by their association with high affinity
binding proteins,
IGFBP-1 to -6. We recently found that, in addition to its ability to bind IGFs,
IGFBP-3 also inhibits IGF-IR activation independently of IGF binding and without interacting directly with IGF-IR. Here, we show that
IGFBP-3 is capable of blocking the signal triggered by IGFs.
Breast carcinoma-derived cells (MCF-7) were stimulated by
des(1-3)IGF-I or [Gln(3),Ala(4),Tyr(15),Leu(16)]
IGF-I, two IGF analogues with intact affinity for IGF-IR, but with weak or virtually no affinity for IGFBPs, then incubated with
IGFBP-3. The activated IGF-IR was desensitized through reversal of its autophosphorylation, following which both
phosphatidylinositol 3-kinase and
p42(MAPK) activities were depressed. Direct measurement of
phosphotyrosine phosphatase activity and reconstitution experiments using
tyrosine-phosphorylated
insulin receptor substrate-1 (IRS-1) indicated that
IGFBP-3 activated a
phosphotyrosine phosphatase (
PTPase). This action appeared to be peculiar to
IGFBP-3 among the IGFBPs, since neither
IGFBP-1 nor
IGFBP-5 (structurally the closest to
IGFBP-3), had any such effect. Several cell lines derived from normal or
tumor cells responsive to
IGF-I were used to show that IGFBP-3-stimulated
PTPase is cell type-specific. Although the precise nature of the
phosphatase remains to be determined, the results of this study demonstrate that
IGFBP-3 stimulates a
phosphotyrosine phosphatase activity that down-regulates the
IGF-I signaling pathway, suggesting a major role for
IGFBP-3 in regulating cell proliferation.