Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles.

Parathyroid hormone-related protein (PTHrP) was first discovered as a circulating factor secreted by certain cancers responsible for the syndrome of humoral hypercalcemia of malignancy. PTHrP possesses distinct paracrine and intracrine signaling roles. The similarity of its N-terminus to that of parathyroid hormone (PTH) enables it to share PTH's paracrine signaling properties, whereas the rest of the molecule possesses other functions, largely relating to an intracrine signaling role in the nucleus/nucleolus in regulating apoptosis and cell proliferation. Recent advances have shown that intracellularly expressed PTHrP is able to shuttle in cell-cycle- and signal-dependent fashion between nucleus and cytoplasm through the action of the distinct intracellular transport receptors importin beta 1 and exportin 1 (Crm1) mediating nuclear import and export of PTHrP, respectively. Together, the import and export pathways constitute an integrated system for PTHrP subcellular localization. Intriguingly, PTHrP nuclear/nucleolar import is dependent on microtubule integrity, transport to the nucleus appearing to occur in vectorial fashion along microtubules, mediated in part by the action of importin beta 1. PTHrP has recently been shown to be able to bind to RNA, meaning that PTHrP's nucleocytoplasmic shuttling ability may relate to a specific role within the nucleus/nucleolus to regulate RNA synthesis and/or transport.