Export of growth factors is generally believed to be restricted to the constitutive secretory pathway, whereas peptide hormones are typically secreted in a regulated manner. Here we show that insulin-like growth factor (IGF)-I, a growth factor released constitutively from the liver, is synthesized and secreted from the mouse pituitary AtT-20 cell line via the regulated pathway. IGF-I production is 1500-fold less than the peptide hormone ACTH. Secretagogue induces IGF-I secretion in a manner similar to ACTH. Like ACTH, IGF-I is sorted into the regulated pathway35-fold more efficiently than a constitutively secreted protein. Dense core granules isolated from cells transfected with a human IGF-I cDNA contain both ACTH and human IGF-I. AtT-20 cells also synthesize IGF-binding proteins, and at least one of these is secreted by the regulated pathway. Human IGF-I does not exhibit milieu-induced, concentration-dependent aggregation, in contrast to secretogranin II which sorts by a proposed aggregation mechanism. These data suggest that 1) growth factors are not solely released from tissues via the constitutive pathway, 2) IGF-I may contain information for correct granular targeting, and 3) IGF-I may be sorted by a mechanism distinct from that proposed for the secretogranins.
