CELL-TYPE-SPECIFIC SECRETION OF PARATHYROID HORMONE-RELATED PROTEIN VIA THE REGULATED VERSUS THE CONSTITUTIVE SECRETORY PATHWAY

Parathyroid hormone-related protein (PTHrP) is endoproteolytically pro cessed to yield a family of mature secretory forms. These include an a mino-terminal, a mid-region, and a carboxyl-terminal form. Prior studi es suggested that the mid-region form is secreted via the regulated se cretory pathway, whereas the amino- and carboxyl-terminal forms are se creted via the constitutive pathway. Further, PTHrP is unusual in that it is produced under normal circumstances by neuroendocrine cell type s as well as by prototypical constitutively secreting cell types. The potential for cell-specific secretory pathway use by PTHrP has not bee n explored. Using immunohistochemical and perifusion techniques, we de monstrate that all three PTHrP daughter peptides are secreted via the regulated pathway in neuroendocrine cells. In contrast, all three daug hter peptides are secreted in a constitutive fashion by non-neuroendoc rine cells. Thus, the secretion of PTRrP is unique in that it appears to be cell-specific. When it is expressed in neuroendocrine cells that contain the regulated pathway, it is secreted in a regulated fashion; when it is expressed in non-neuroendocrine cells, it defaults to the constitutive pathway. This phenomenon has not previously been describe d for a polypeptide hormone in naturally occurring cells.