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Department of Foods and Nutrition and the Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN 47907
3To whom correspondence should be addressed. E-mail: fleet{at}purdue.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • kinase • ion flux • vitamin D
Vitamin D has been viewed as a prohormone produced in the skin that regulates calcium metabolism after metabolic conversion in the liver and kidney to its hormonally active form, 1,25 dihydroxyvitamin D [1,25(OH)2 D].4 When 1,25(OH)2 D interacts with the vitamin D receptor (VDR) it induces heterodimerization of VDR with the retinoid X receptor (RXR), DNA binding of the heterodimer to vitamin D response elements, and recruitment of various coactivators leading to the enhanced transcription of genes whose protein products control calcium homeostasis [e.g., transient receptor potential vanilloid-type family member 6 (TRPV6), osteocalcin, 25 hydroxyvitamin D, 24 hydroxylase (CYP24)] (1). However, this model is being expanded by a variety of observations. First, vitamin D insufficiency has been observed in various subpopulations, which suggests that vitamin D is a required nutrient for some individuals (e.g., dark-skinned individuals, the elderly, and people who receive limited sunlight exposure (2). Second, the inverse association of vitamin D status with the occurrence of a wide variety of chronic diseases (e.g., cancer, diabetes) demonstrates that controlling calcium metabolism represents only a portion of the biological actions of vitamin D (2). Third, the identification of extrarenal 1
hydroxylases suggests that 1,25(OH)2 D may act as an autocrine or paracrine signal in addition to its traditional endocrine role (3). Finally, rapid, transcription-independent events have been observed in response to physiologic levels of hormone. This suggests that a more complex mechanism mediates vitamin D action than that represented in the traditional ligand-activated transcriptional model.
Regarding this last point, there is now compelling evidence for the existence of 1,25(OH)2 D-inducible signal transduction pathways within various cell types. The history of this field has been previously reviewed in other reports and interested readers are encouraged to refer to those reviews (4,5) and to early reports of historical interest (6–9). However, a brief summary of this work shows that 1,25(OH)2 D rapidly (within seconds and minutes) stimulates events normally associated with the activation of membrane receptors for growth factors and peptide hormones. These include: 1) phospholipase C (PLC) and phospholipase D activity; 2) phosphoinositide turnover leading to the generation of the second messengers inositol 1,3,4-triphosphate (IP3) and 1,2-diacylglycerol (DAG); 3) intracellular calcium by increasing calcium uptake and the release of intracellular calcium stores; 4) adenylate cyclase activity to increase cAMP levels and stimulate protein kinase A (PKA) activity; 5) calcium-dependent protein kinase C (PKC) isoform activity (, ß, 
) and cellular redistribution; and 6) Jun activated kinase and extracellular response activated kinase (ERK) mitogen activated protein kinase (MAPK) family activation (4,5,10). The effect of 1,25(OH)2 D treatment on signal transduction pathways may depend upon adequate vitamin D status; rapid 1,25(OH)2 D-induced changes in phosphoinositide turnover, PKC translocation, and changes in intracellular calcium do not occur in colonocytes from vitamin D-deficient, hypocalcemic rats (11). Rapid activation of signal transduction pathways has also been observed for the other steroid hormones, e.g., estrogen, androgen, glucocorticoids (12). This suggests that viewing vitamin D (and other steroid hormone) biology through the prism of the traditional, nuclear receptor-mediated transcriptional responses is limited.
In this short review, I summarize some of the recent work that sheds light on the mechanism of how the rapid actions of 1,25(OH)2 D are initiated at the plasma membrane, I try to put these responses into a physiologic context, and I identify the questions that need to answered by future research.
Initiation of Rapid Actions at the Plasma Membrane.
One debate that has occupied scientists within this area is how the rapid signaling process is initiated. Is there a unique receptor for the 1,25(OH)2 D at the plasma membrane that functions similarly to the growth factor and peptide hormone receptors (i.e., membrane spanning with inherent kinase activity)? Or is rapid signaling a unique role for the traditional VDR? The idea that there might be a unique membrane receptor for 1,25(OH)2 D originates from 2 observations: 1) there are vitamin D analogs that have limited ability to bind to the classical VDR but which can still stimulate the rapid actions of vitamin D (13,14) and 2) there is a binding protein for 1,25(OH)2 D in the basolateral membrane of rat and chick enterocytes and this protein is distinct from the VDR [i.e., based on partial purification and sequencing, higher KD for 1,25(OH)2 D binding than VDR (15)]. Recently Norman et al. (12) proposed that analogs that stimulate the rapid actions of vitamin D may bind to an alternate pocket within the traditional VDR, so the analogue studies may no longer be clear proof of the existence of a distinct membrane receptor. However, the identity of the plasma membrane 1,25(OH)2 D binding activity, now called the membrane-associated rapid response steroid binding (MARRS) protein, was recently revealed to be a multifunctional, thioredoxin-like protein also known as GRP58 (for glucose responsive protein, 58 kDa) or endoplasmic reticulum protein 57/60 kDa (ERp57 or ERp60) (16). Studies with an inhibitory antibody or with ribozymes to reduce cellular MARRS levels in osteoblasts and chick enterocytes demonstrate that this protein has a role in 1,25(OH)2 D-stimulated uptake of phosphate (in the chick enterocyte), intracellular calcium flux (in osteoblasts), and activation of PKC (16,17). Surprisingly, this protein is not a traditional membrane spanning receptor nor is its localization limited to the plasma or basolateral membrane. Sequence analysis shows that membrane association is more likely due to the presence of a myristoylation sequence in the protein. In addition to localization of the MARRS protein at the plasma membrane, it is also found at the endoplasmic reticulum, and 1,25(OH)2 D treatment induces a redistribution of the MARRS protein from these sites to the nucleus (18). While this doesn’t fit our classic description of membrane receptors that mediate signal transduction pathways, data from Schwartz et al. (19) indicate that MARRS has a VDR-independent action on PKC activation in matrix vesicles of growth zone chondrocytes. In these nucleus-free vesicles involved in cartilage calcification, Schwartz et al. found that 1,25(OH)2 D activates PKC by activating PLC ß1 and ß3 through the G-protein Gq. These matrix vesicles did not contain the traditional VDR and the effect of 1,25(OH)2 D was inhibited by an antibody against the MARRS protein. Similarly, the rapid activation of PLC and PKC by 1,25(OH)2 D that is normally observed in growth zone chondrocytes was not reduced in cells from VDR null mice (20). While this demonstrates that at least some of the plasma membrane initiated actions of 1,25(OH)2 D are mediated through MARRS, it is not yet clear whether MARRS directly interacts with G-proteins or other mediators of signal transduction pathways.
Evidence for the Traditional VDR.
Even as evidence on the importance of the MARRS protein has accumulated, there is growing direct evidence that the traditional VDR may also have a unique, nontranscriptional role in mediating plasma membrane initiated signaling. The most critical evidence supporting this model is that several groups have demonstrated that 1,25(OH)2 D-induced rapid actions are lost in osteoblasts from VDR knockout mice (21) or fibroblasts from patients with type II rickets (9,22). In addition, Huhtakangas et al. (23) recently used biochemical methods and immunodetection to identify VDR within caveoli in a variety of cell types (e.g., intestine, kidney, lung, leukemia cells, and osteoblast-like cells). While others had previously observed a 1,25(OH)2 D-induced translocation of VDR to the plasma membrane of skeletal muscle cells (24), this was the first report of VDR associated with the lipid raft-rich areas of the plasma membrane where the caveoli protein caveolin is known to interact with the nonreceptor tyrosine kinase Src, the G-protein G subunits, and the central kinase h-Ras (25). Thus VDR is in close proximity to essential components of the signal transduction system.
The existence of VDR at the plasma membrane and the activation of ion fluxes and kinase responses following 1,25(OH)2 D treatment suggest that the VDR will interact with G-proteins and nonreceptor tyrosine kinases that are proximal mediators of signal transduction pathways. However, at this time there is no direct evidence for the interaction of VDR with G-proteins. In contrast, Buitrago et al. (26) have shown that activation of the nonreceptor tyrosine kinase Src coincides with a 1,25(OH)2 D-induced interaction between Src kinase and VDR in chick muscle cells. This is consistent with an earlier report in human keratinocytes showing 1,25(OH)2 D-induced Src kinase activation, stimulation of interactions between Src- and the signaling adapter protein Shc that lead to phosphorylation of Shc, and formation of a complex including the Shc adapter, VDR, a second signaling adapter protein (Grb2), and the Ras kinase activator mSos in cells grown in high calcium medium (27,28). Activation of Src and the formation of these complexes are known to be proximal steps that can lead to the activation of the MAPK ERK1/2 (29) and phosphatidylinositol 3 kinase (30).
The interaction between Src and VDR is likely mediated through phosphorylation of an essential tyrosine residue between amino acids 160 and 174 on the chick VDR that permits interaction with the SH2 domains in Src (a putative tyrosine phosphorylation site at position 147 is conserved in both human and mouse VDR but phosphorylation of that site has not yet been confirmed). A recent study by Barletta et al. (31) shows that in addition to Src-estrogen receptor (ER) interactions through the SH2 domain of Src, ER uses a protein called modulator of nongenomic activity of the estrogen receptor (MNAR) as a docking protein to the SH3 domain of Src. Since MNAR binds to ER through the same LXXLL amino acid motif that the p160, p300, and mediator family of transcriptional coactivators use to bind steroid hormone receptors (including VDR), this may be a common protein used by all steroid hormone receptors during membrane-initiated signaling. This model and a summary of the downstream events initiated by rapid vitamin D signaling are presented in Figure 1.
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Two other processes are strong candidates for regulation by rapid, membrane initiated signaling. The first is cell proliferation. Bettoun et al. (34) recently reported that in the intestinal cell line Caco-2, VDR is associated with the catalytic subunit of the protein phosphatases PP1c and PP2Ac and that ligand binding induces the activity of these phosphatases. This activation results in the phosphorylation and inactivation of p70S6 kinase, an enzyme that is crucial for the G1-S transition in the cell cycle. This represents an early step in the growth inhibitory actions of vitamin D that is likely followed by VDR-mediated transcriptional activation of genes like the cyclin-dependent kinase-inhibitor p21 (35) and the insulin-like growth factor 1 antagonist, IGF-binding protein 3 (36).
Another possible role for rapid 1,25(OH)2 D signaling may be to optimize the genomic actions of the hormone that are mediated through the VDR. For example, pharmacologic suppression of PKC activity inhibited 1,25(OH)2 D-regulated CYP24 gene expression in proliferating, small intestine crypt-like, rat IEC-6 cells (37) and activation of PKC with phorbol esters enhanced 1,25(OH)2 D-regulated CYP24 mRNA induction in IEC-6 and IEC-18 cells (38). ERK 1, 2, and 5 kinases have recently been shown to be critical regulators of 1,25(OH)2 D-mediated CYP24 promoter activity in COS-1 kidney cells (39). Similar findings in support of cross-talk between the rapid and genomic actions of 1,25(OH)2 D have been observed for 1,25(OH)2 D-mediated osteocalcin promoter activity in the osteoblast-like cell ROS 17/2.8 (40), c-myc mRNA levels in proliferating skeletal muscle (29), and CYP3A4 mRNA levels in proliferating Caco-2 cells (41).
Cross-talk between the 2 modes of 1,25(OH)2 D signaling is likely mediated through the targeted phosphorylation of critical proteins in the VDR-containing transcriptional complex. Phosphorylation of serine 208 (S208) in VDR by the nuclear kinase, casein kinase II, is increased after 1,25(OH)2 D treatment of COS-7 cells (42,43) and this may be necessary for coactivator recruitment to the nVDR-RXR heterodimer (44). Dwivedi et al. (39) proposed that ERK 1 and 2 influence CYP24 reporter gene activity in Caco-2 cells through phosphorylation of RXR at serine 260 while ERK5 modulates vitamin D-mediated CYP24 induction through phosphorylation of the Ets transcription factor. Other studies suggest that the proteins that influence chromatin structure are phosphorylation targets. Recently Shen et al. (45) showed that 45 min of treatment with 10 nmol/L calcitriol increased histone H3 phosphorylation in the nucleus of ROS 17/2.8 cells. Gusterson et al. (46) have shown that activation of genes that depend upon the transcriptional coactivators CBP and p300 is enhanced by ERK1/2-mediated phosphorylation in cardiac cells. Rowan et al. (47) identified 4 functional MAPK phosphorylation sites in steroid receptor co-activator 1 (SRC1); 2 of these sites (serine 1185, threonine 1179) lie within a region that is known to interact with cyclic AMP regulatory element binding protein-binding protein (CBP)/p300. This interaction was recently shown to be crucial for thyroid hormone receptor ß-mediated gene transcription (48) but it is not yet clear whether 1,25(OH)2 D-activated, MAPK-mediated, phosphorylation of CBP, p300, or SRC1 occurs and whether this phosphorylation modulates CBP/p300-SRC1 interactions or binding of this complex to the VDR-RXR heterodimer.
Major Remaining Questions. Although the area of membrane-initiated vitamin D action has advanced dramatically in the past 15 y, there are still a number of important questions and issues that need to be resolved. First and foremost, the membrane initiated signaling system needs to be more extensively characterized in a wider variety of cell types and species. The current model exists only by combining pieces of data from multiple species and multiple cell types. The most complete data currently comes from chick muscle cells and from rat chondrocytes. Because several groups have reported opposing actions of 1,25(OH)2 D on endpoints like MAPK activation [e.g., activation in human Caco-2 (10), inhibition in tumor-derived mouse endothelial cells (49)], understanding cell type, cell stage, and species differences may be critical to a complete understanding of the role of 1,25(OH)2 D signaling in health. Beyond simple characterization efforts, we also need to better understand whether rapid vitamin D actions influence unique physiologic processes (e.g., as suggested by data from chondrocytes) or whether the traditional VDR is a critical component of both the rapid and the transcriptional actions of 1,25(OH)2 D. The data from VDR null mice demonstrate that the VDR is critical for intestinal calcium absorption and hair follicle development (50,51). However, the possibility that rapid vitamin D actions modify these and other processes has not yet been excluded. In a similar vein, what role do rapid vitamin D actions have when the current evidence suggests that serum 1,25(OH)2 D levels are stable and adapt over the course of hours and days rather than minutes and seconds (52)? Have we not looked at this issue in fine enough detail or could local production of 1,25(OH)2 D and paracrine/autocrine signaling (which may not be observed systemically) be a critical component of rapid vitamin D signaling? These and other questions will continue to drive this field for the foreseeable future.
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FOOTNOTES |
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2 Supported by funds from the National Institutes of Health: awards DK-54111 and CA-101113 to J.C.F.
4 Abbreviations used: 1,25(OH)2 D, 1,25 dihydroxyvitamin D; CBP, cyclic AMP regulatory element binding protein-binding protein; CYP24, 25 hydroxyvitamin D, 24 hydroxylase; DAG, 1,2-diacylglycerol; ER, estrogen receptor; ERp, endoplasmic reticulum protein; ERK, extracellular response activated kinase; IP3, inositol 1,3,4-triphosphate; MAPK, mitogen activated kinase; MARRS, membrane-associated rapid response steroid binding; MNAR, modulator of nongenomic activity of the estrogen receptor; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PP, protein phosphatase; RXR, retinoid X receptor; SRC1, steroid receptor coactivator 1; TRPV6, transient receptor potential vanilloid-type family member 6; VDR, vitamin D receptor.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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