Parathyroid Hormone-Related Protein as a Prohormone: Posttranslational Processing and Receptor Interactions*

Abstract

Since the elucidation of the structures of the three human PRHrP isoforms in 1987, information has rapidly accured which indicates that the role of PTHrP in normal physiology will prove to be crucial as well as exceedingly complex. The importance of the role of PTHrP in normal physiology is underscored by its broad tissue expression, by its intense evolutionary conservation, by its extremely early expression after fertilization of the ovum, and by the lethal consequences of PTHrP gene disruption. The complexity of the role of PTHrP in normal physiology increases almost monthly. This complexity is reflected in the broad tissue distribution of the peptide, its complex transcriptional regulation and mRNA instability motifs, and its multiple transcripts and isoforms. It is now clear that additional complexity exists at the level of posttranslational processing. Expression of the PTHrP gene leads to the tissue-specific processing and secretion of an increasingly complex family of derivative peptides, each with its own repertoire of cognate receptors, signal transduction pathways, and physiological consequences. Further elucidation of the posttranslational processing pathways and mechanisms can be anticipated in the coming years, coupled with a corresponding elucidation of multiple PTHrP receptors, their specific signal transduction pathways, and their unique physiological roles. The role of PTHrP in causing HHM is now clearly established. Work in the coming decade will focus on the normal physiological roles played by PTHrP.

The N- and C-terminal domains of parathyroid hormone-related protein affect differently the osteogenic and adipogenic potential of human mesenchymal stem cells

“…These three peptides are identical in positions 1-139 and differ only in their carboxy termini. The three initial PTHrP translation products undergo extensive posttranslational processing and give rise to a family of mature secretory forms of the peptide, each with its own physiological function (s) and each with its own receptor or receptors (Orloff et al, 1994). For example, the amino-terminal PTHrP secretory form, PTHrP , shares N-terminal homology with PTH and acts through same PTH type 1 receptor (PTH1R) (Juppner et al, 1991); thereby initiating multiple events (e.g.…”

Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells

“…19 for review). One of the mature secretory forms is the N-terminal PTH-like PTHrP- , which binds to PTHR1.…”

PTHrP Produced by Myeloma Plasma Cells Regulates Their Survival and Pro-Osteoclast Activity For Bone Disease Progression

“…Furthermore, by using rabbit anti-mid-region PTHrP, we specifically revealed a single band of approximately 7 kDa related to the mid-region, as described for other tumors. (9)(10)(11)(23)(24)(25) We also measured RNA levels of both PTHrP and PTH-R1 (Fig. 1D) in selected plasma cell samples, based on the highest cytometric expression.…”

“…(22) The functional role of PTHrP fragments in human pathophysiology has been intensively investigated and their generation by posttranslational proteolysis of members of the subtilisin family, has been definitely assessed. (23)(24)(25) Tumors producing skeletal metastases are usually associated with high PTHrP activity that apparently correlates with poor prognosis in both breast and prostate cancers, (13) although a survival advantage has been unexpectedly described in female patients with lung adenocarcinoma and serum elevation of PTHrP. (26) Nevertheless, the role of PTHrP on cancer growth has been definitely confirmed by demonstrating that its suppression, by either neutralizing antibodies in MDA-MB-231 breast cancer cells or by antisense oligonucleotides in mouse models, restrains tumor progression, resulting in marked reduction of tumor size.…”