Affinity for the insulin-like growth factor-II (IGF-II) receptor inhibits autocrine IGF-II activity in MCF-7 breast cancer cells.
We have investigated the autocrine regulation of insulin-like growth factor-II (IGF-II) signaling by the insulin-like growth factor-I receptor (IGF-IR) and the insulin-like growth factor-II/mannose 6-phosphate receptor (IGF-IIR) in MCF-7 breast cancer cells, employing retroviruses encoding both IGF-I, IGF-II, and IGF-I and II mutants with reductions in affinity for either the IGF-IR or the IGF-IIR. These studies revealed reciprocal roles for IGF-IR and IGF-IIR affinity in the regulation of autocrine IGF-II activity. IGF-IR affinity was required for serum-free proliferation but also for efficient IGF-II secretion. In contrast, cellular proliferation, receptor tyrosine kinase-dependent signaling, and extracellular IGF-II protein accumulation were all reduced in the presence of IGF-IIR affinity. Inhibition of IGF-II signaling appeared to be the sole consequence of IGF-IIR affinity, as no cellular responses attributable to selective IGF-IIR binding by a reduced IGF-IR affinity IGF-II mutant could be detected. By operating as an IGF-II antagonist, the IGF-IIR has tumor suppressor-like properties, a suggestion consistent with reports of loss of heterozygosity at the IGF-IIR locus in a variety of human malignancies.
Ellis
M J
MJ
Vincent T Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C, USA.
Leav
B A
BA
Yang
Z
Z
Rasmussen
A
A
Pearce
A
A
Zweibel
J A
JA
Lippman
M E
ME
Cullen
K J
KJ
D000595:Amino Acid Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000473:pathology*; D002455:Cell Division; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D016895:Culture Media, Serum-Free; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1