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Minireview: Parathyroid Hormone-Related Protein as an Intracrine Factor—Trafficking Mechanisms and Functional Consequences

Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15217

Address all correspondence and requests for reprints to: Nathalie Fiaschi-Taesch, Division of Endocrinology and Metabolism, Biomedical Science Tower E-1140, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, Pennsylvania 15213. E-mail: taeschn{at}msx.dept-med.pitt.edu.

	Abstract

Top Abstract Introduction How Does a Secretory... What Are the Mechanisms... What Are the Consequences... Conclusion References

 
PTH-related protein (PTHrP) was originally discovered as the factor responsible for humoral hypercalcemia of malignancy. PTHrP is produced by most cell types and is a prohormone that gives rise to a family of mature secretory forms arising from posttranslational endoproteolytic cleavage of the initial translation product. Each of these secretory forms of PTHrP is believed to have one or more of its own receptors on the cell surface that mediates the normal paracrine, autocrine, and endocrine actions of PTHrP. Recently, evidence has accumulated that indicates that PTHrP is also able to enter the nucleus and/or the nucleolus and influence cellular events in an intracrine fashion. This review discusses the mechanisms by which PTHrP may gain access to the nucleus/nucleolus and the functional consequences of this nuclear entry by PTHrP.

	Introduction

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PTH-RELATED PROTEIN (PTHrP) was originally identified as the factor responsible for the syndrome of humoral hypercalcemia of malignancy (1, 2, 3). Soon after its discovery, it became apparent that PTHrP is ubiquitously produced and secreted in normal and malignant cells (4). PTHrP is known to be a critical regulator of cellular and organ growth, development, migration, differentiation, and survival, and of epithelial calcium ion transport (4). These effects are accomplished in part by autocrine/paracrine actions of several secreted forms of PTHrP on cell surface receptors (Fig. 1). In addition to these well recognized and classical autocrine/paracrine roles, PTHrP has been observed to have intracrine actions as well, entering the nucleus under the direction of a nuclear localization signal (NLS) (Figs. 1 and 2). This NLS is composed of multibasic amino acids in the 88–106 region of the peptide. Recently, we and others (5, 6) have demonstrated that the NLS is both necessary and sufficient for the nuclear localization of PTHrP.

View larger version (7K): [in this window] [in a new window]   Figure 1. Structural map of the native PTHrP (1–139) initial translation product. The small numbers above vertical lines indicate the sites of basic amino acids (arginines or lysines) that serve as either prohormone convertase sites or NLS. The precise borders of the NLS are not defined but include the 88–106 region. The large arrow shows the classical translational start site, and the smaller arrows the potential alternative translational start sites within the signal peptide. The three principal secretory forms of PTHrP are PTHrP (1–36), PTHrP (38–94), and PTHrP (107–139).

View larger version (72K): [in this window] [in a new window]   Figure 2. Immunocytochemistry showing nuclear staining in PTHrP-overexpressing A-10 cells (right, x200; left, x400). Note that the pattern is a diffuse reticulated pattern and that the two most prominent nuclei are in a single dividing cell. Negative controls (no primary antibody and competition with excess PTHrP) revealed no staining (from Ref. 30 ).

	How Does a Secretory Protein Like PTHrP Develop Access to the Cytoplasm for Subsequent Targeting to the Nucleus?

Top Abstract Introduction How Does a Secretory... What Are the Mechanisms... What Are the Consequences... Conclusion References

 
PTHrP is normally a secretory protein that enters the endoplasmic reticulum (ER) under the direction of its signal peptide (Fig. 1) following translation on ribosomes. To enter the nucleus from the cytoplasm, PTHrP must therefore: 1) be secreted and then re-enter the cell by endocytosis; 2) never enter the ER, but remain in the cytoplasm where it can directly access the nuclear pore; or, 3) travel retrograde from the ER, back into the cytosol, and then enter the nucleus. There is evidence to support each of these possibilities, discussed below.

Secretion and endocytosis
One mechanism through which a secretory protein might access the cytoplasm and nucleus following secretion could be an endocytosis-dependent pathway (Fig. 3A). Examples of cell surface receptor-activating polypeptide hormones, growth factors, and cytokines that can localize to the nucleus together with their receptor are increasingly recognized (8, 9, 10). Examples include platelet-derived growth factor; fibroblast growth factor (FGF) 1 and 2; epidermal growth factor; ILs 1, 1ß, and 2; GH; angiogenin; and angiotensin (9, 10). The receptor for the amino terminus of PTHrP is the PTH receptor (PTH1R). Endocytosis of PTH1R-ligand complex has been demonstrated (11, 12, 13). In one study, Lam et al. (13) showed that, using PTH1R-expressing rat osteoblast cells (UMR 106.01), preincubating cells with a fluorescently tagged PTHrP internalized the PTHrP with subsequent transport and localization to the nucleus. They proposed that the internalization of PTHrP occurs through the PTH1R because preincubation of the cells with excess unlabeled PTHrP prevented the cells from internalizing the labeled PTHrP due to the down-regulation of the receptor by prior internalization (13). However, other studies do not support this concept. Using Chinese hamster ovary cells overexpressing the PTH1R, Amizuka et al. (14) were unable to demonstrate nuclear staining for PTHrP after addition of PTHrP to the culture medium. It is also possible that endocytosis of PTHrP could be mediated by a receptor distinct from the PTH1R. In a recent study, Aarts et al. (15) showed that full-length PTHrP (1–141) secreted from COS-1 cells transfected with PTHrP can be endocytosed and targeted to the nucleus. This endocytosis was NLS dependent but did not require the PTH1R. Finally, the possibility that an endocytosed form of PTHrP could reach the nucleus by binding to an intracellular form of the PTH1R may exist because a novel splice variant of the PTH1R, which preferentially localizes to the cytoplasm, has been described (16).

View larger version (30K): [in this window] [in a new window]   Figure 3. Potential pathways used by PTHrP to access to the cytoplasm for subsequent targeting to the nucleus. A, Secreted PTHrP can either bind to PTH1R, be internalized and have access to the nucleus; or secreted PTHrP can be endocytosed and targeted to the nucleus via a PTH1R-independent mechanism. B, Direct translocation of PTHrP may involve alternative initiation of translation at non-AUG codons. This results in signal peptide-truncated forms of PTHrP which remain in the cytoplasm and translocate to the nucleus. C, PTHrP once in the ER, may translocate back to the cytoplasm by specific ER sequestering proteins, chaperones, or receptors ( ), and from there access the nucleus.

Retrograde trafficking from ER to the nucleus
Finally, a third plausible mechanism for intracrine translocation of PTHrP to the nucleus is retrograde translocation of the protein from the endoplasmic reticulum by specific carrier proteins (Fig. 3C; Ref. 7). According to recent studies, a new concept has emerged in which a secreted protein can reverse translocate from the ER to the cytoplasm (20). Evidence suggests that misfolded proteins that would classically undergo degradation in the ER, can also be back-translocated from the ER to the cytoplasm and then be degraded by cytoplasmic ubiquitin-proteasomes (20). The fact that PTHrP has been recognized as a secretory protein that undergoes proteolysis through the ubiquitin-proteosome pathway argues for such a hypothesis (21, 22). Thus, it is conceivable that, under some circumstances, PTHrP within the ER may be translocated back to the cytoplasm by specific ER sequestering proteins or chaperones, and from there have access to the nucleus without proteasomal degradation. The observation that the expression of a PTHrP construct containing only the classical translational AUG initiation codon in Chinese hamster ovary cells is targeted to both the secretory pathway as well as to the nucleus is in accord with that possibility (14).

	What Are the Mechanisms Regulating PTHrP Entry into the Nucleus?

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Nuclear transport of PTHrP depends on microtubule integrity
More recent studies, using a PTHrP-green fluorescent protein fusion and fluorescence recovery after photobleaching, suggest that PTHrP can shuttle in both directions between cytoplasm and nucleus via the nuclear pore complex and demonstrated that microtubule integrity plays an important role in PTHrP nuclear import (23). The role of microtubules in PTHrP subcellular localization was indicated by the demonstration of colocalization with ß-tubulin, and the fact that the microtubule-disrupting agent, nocodazole, alters the level of PTHrP nuclear accumulation and its nucleocytoplasmic flux. Interestingly, another study by Lam et al. (24) shows that, in living cells, PTHrP is exported from the nucleus in a leptomycin B-sensitive manner, implicating CRM1 (exportin 1/Xpo1p/Kap124p) as the PTHrP nuclear export receptor. This finding suggests that PTHrP nucleocytoplasmic-flux occurs through distinct import and export receptors. Inhibiting nuclear export by leptinomycin B also reduces the nuclear import of PTHrP, indicating that net PTHrP subcellular localization is the result of an integrated regulatory system (24).

Nuclear import is regulated by phosphorylation of Thr⁸⁵ and involves importin ß
The nuclear import of many regulatory proteins appears to be used by mammalian cells to trigger transition through the cell cycle. This involves a series of phosphorylation/dephosphorylation events on a number of proteins. Sequence comparisons show that many transcriptional regulatory proteins such as Simian virus-40 T-antigen, p53 and c-abl contain domains, adjacent to their NLS, for p34^cdc2 kinase phosphorylation (25). PTHrP possesses such a concensus motif for phosphorylation by p34^cdc2 kinase immediately upstream the NLS at Thr⁸⁵. Recent studies provide in vitro evidence that PTHrP may indeed be a phosphorylation substrate for p34^cdc2 kinase at Thr⁸⁵ (13, 26). Moreover, Lam et al. have reported that phosphorylation at Thr⁸⁵ prevents its nuclear import. In contrast to most other nuclear imported proteins, in the Lam studies (26), PTHrP nuclear import appeared to be mediated almost exclusively by the saturable transport receptor, importin ß, and not by importin .

Nuclear vs. nucleolar targeting
Endogenous PTHrP has been localized to the nuclear compartment in cell lines, tumors, and normal tissue using a variety of specific antibodies which detect distinct epitopes within PTHrP. Henderson et al. (6, 27), as well as others (23, 24, 28, 29), have suggested that when PTHrP enters the nucleus, it is principally observed in the nucleolar compartment. In contrast, we and others (5, 30, 31) have observed PTHrP principally in a diffuse nuclear pattern (Fig. 2). The reasons for the nuclear vs. nucleolar predominance in these various studies require clarification. It is possible that the pattern may be cell-type specific, appearing principally in the nucleus in certain cell types and principally in the nucleolus in other cell type. It is also possible that this difference represents differences in antisera employed, epitope tag employed, or species differences.

Cell cycle-dependent regulation of PTHrP localization in the nucleus and nucleolus
A number of studies suggest that nuclear translocation of PTHrP is cell cycle dependent. In the human keratinocytes cell line, HaCaT, Lam et al. (29) observed PTHrP in the nucleolus in G₁, but it relocalized to the cytoplasm in mitotic cells. In contrast, we reported that untransfected and PTHrP-overexpressing A10 vascular smooth muscle cells display PTHrP immunoreactivity primarily in the nuclei of cells that were dividing or were in the process of completing cell division (G₂ or M; Fig. 2), suggesting that nuclear translocation is associated with activation of the cell cycle (30). Whether these differences are a reflection of the methodology employed or are cell-type specific and reflect distinct nuclear actions of PTHrP remain to be defined.

	What Are the Consequences of Nuclear Entry of PTHrP on Cellular Function?

Top Abstract Introduction How Does a Secretory... What Are the Mechanisms... What Are the Consequences... Conclusion References

 
Nuclear partner(s) for PTHrP?
Identifying the potential partners of nuclear PTHrP will be crucial for understanding the nuclear actions of PTHrP. These partners or targets could in theory be RNA, DNA, or another protein. For example, Aarts et al. (15, 28) suggest that PTHrP has mRNA binding properties in vitro through a consensus lysine motif present in the NLS. These observations suggest a possible role for PTHrP, perhaps in conjunction with other proteins, as a nuclear export factor for mRNA, consistent with its ability to shuttle between nuclear/nucleolar and cytoplasmic compartment. RNA binding by PTHrP also has been suggested to contribute to its cytoskeletal association because a large component of cytoplasmic mRNA appears associated with cytoskeletal elements (32).

The fact that the PTHrP NLS is homologous to that in other transcription factors such as c-jun, c-fos, and p53 that directly bind DNA suggests that PTHrP could also be a transcription factor that directly binds DNA. No experimental evidence exists at present to support this possibility.

Finally, it is possible, and indeed likely, that PTHrP may bind other nuclear or cytoplasmic protein that are required to implement its nuclear actions. This is an active area of investigation in a number of laboratories.

Functional consequences of nuclear entry by PTHrP
Three physiologic or biologic functions of nuclear/nucleolar translocation of PTHrP have been demonstrated to date. It appears from data available that the physiological consequences of nuclear PTHrP entry vary from one cell type to another. Interestingly, increasing evidence indicates that the secreted and nuclear forms of PTHrP may have distinct, and at times completely opposite, effects on cellular function. Examples of physiologic responses to nuclear/nucleolar PTHrP are as follows. First, Henderson et al. (6) have provided evidence that chondrocytes overexpressing PTHrP with an intact NLS prolongs their survival under conditions of serum starvation-induced cell death (6). Similar observations have been reported for the breast cancer cell line MCF-7. Cells overexpressing PTHrP with an intact NLS were protected from serum starvation-induced apoptosis and were enriched in G₂ + M stage of the cell cycle (33). Secondly, in vascular smooth muscle cells (VSMCs), exogenous (i.e. paracrine or autocrine) PTHrP inhibits proliferation, whereas gene transfer (i.e. intracrine, nuclear) of PTHrP is associated with activation of cellular proliferation (5, 30). Deletion of the NLS region of PTHrP dramatically inhibits both nuclear localization as well as proliferation of VSMCs. Moreover, in VSMCs of the PTHrP knockout mouse, proliferation is reduced (30). These observations collectively indicate that nuclear PTHrP targeting is required for normal embryonic smooth muscle cell proliferation. In addition to the NLS, activation of proliferation in VSMCs requires both an intact NLS and carboxy-terminal region of PTHrP (5). Third, PTHrP has been demonstrated in prostate cancer cells, via an intracrine pathway, to induce production of IL-8 (31), a potent angiogenic factor contributing to tumorigenic activity in several cancers. This action appears to be independent of the classical NLS. This novel action of nuclear PTHrP could mediate its effects on the progression of prostate cancer.

	Conclusion

Top Abstract Introduction How Does a Secretory... What Are the Mechanisms... What Are the Consequences... Conclusion References

 
PTHrP is an extraordinary protein. It is an ubiquitously expressed protein that is essential for life. It is a classical neuroendocrine peptide that undergoes extensive posttranslational processing before secretion. The several secreted forms of PTHrP have a broad range of effects in many organs involving development, survival, and function. Just when we were getting comfortable, believing we understood the broad outlines of PTHrP physiology and mechanisms of action, we learn that it operates in a second completely distinct manner that involves nuclear import and action. Future work defining nuclear role of PTHrP, understanding the mechanisms through which PTHrP enters the nucleus, and defining the partners of PTHrP in the nucleus, have become essential for completely understanding the biology of this complex but essential protein. Findings arising from these studies will certainly have important implications for our understanding of PTHrP as a signaling protein during fetal development, as an oncoprotein during the progression of tumors, and in addition, as regulator of vascular wall remodeling, with potential therapeutic applications.

	Acknowledgments

 
We thank Drs. Rupangi Vasavada, Adolfo Garcia-Ocaña, Thierry Massfelder, Jean-Jacques Helwig, Andrew Karaplis, and Thomas Clemens for their stimulating discussions.

	Footnotes

 
This work is supported by NIH Grant RO-1-DK-54308.

Abbreviations: ER, Endoplasmic reticulum; FGF, fibroblast growth factor; NLS, nuclear localization signal; PTH1R, PTH receptor; PTHrp, PTH-related protein; VSMCs, vascular smooth muscle cells.

Received August 6, 2002.

Accepted for publication November 5, 2002.

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