Signaling Cross-talk from Gβ4 Subunit to Elk-1 in the Rapid Action of Androgens

Zagar, Yvrick; Chaumaz, Gilles; Lieberherr, Michèle

doi:10.1074/jbc.m309132200

Cited by 38 publications

(31 citation statements)

References 66 publications

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“…In the current study, we used these readouts and biochemical inhibitors to demonstrate that G␣ i , PI3K, PKC, Src, and Ras/Raf/MEK/ERK pathways are downstream effectors of GPRC6A. These results resemble non-genomic responses to testosterone observed in macrophages and osteoblasts that also involve activation of PI3K, PKC, c-Src, cRaf-1, and MEK1/2 via a putative pertussis toxin-sensitive G-protein (53,54). Our findings, however, do not exclude the existence of other molecular targets or other signal transduction pathways that may also mediate the non-genomic actions of sex steroids.…”

Section: Discussionmentioning

confidence: 72%

“…Many tissues are purported to have non-genomic responses to androgens, including endothelial cells, osteoblasts, skeletal muscle cells, synaptosomes, prostate cells, T cells, and macrophages (17,54,56,57). Non-genomic effects of GPCRs have been implicated in a variety of physiological processes, including anesthetic and antiepileptic actions, changes in neuronal activity, neurodegenerative diseases, facilitation of the sperm acrosome reaction, oocyte maturation, insulin sensitivity in adipocytes, endothelial dysfunction, and vasodilation (58 -63), but none of these have been confirmed by loss-of-function of the non-genomic molecular target.…”

Section: Discussionmentioning

confidence: 99%

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GPRC6A Mediates the Non-genomic Effects of Steroids

Parrill

Quarles

2010

Journal of Biological Chemistry

169

143

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The identity of the putative G-protein coupled receptor (GPCR) that mediates the non-genomic effects of androgens is unknown. We present in vitro and in vivo evidence that the orphan GPRC6A receptor, a widely expressed calcium and amino acid sensing GPCR, transduces the non-genomic effects of testosterone and other steroids. Overexpression of GPRC6A imparts the ability of extracellular testosterone to illicit a rapid, non-genomic signaling response in HEK-293 cells lacking the androgen receptor. Conversely, testosterone-stimulated rapid signaling and phosphorylation of ERK is attenuated in bone marrow stromal cells derived from GPRC6A Androgens are important regulators of reproductive physiology and anabolic biological activities in multiple tissues (1). In addition, androgens also play a role in the pathogenesis of prostate cancer, including disease severity, progression, and metastasis (2, 3). The classical genomic actions of androgens are mediated through the androgen receptor (AR), 3 a member of the nuclear receptor superfamily of transcription factors (4 -6). Androgen binding to AR and translocation of the steroid-receptor complex to the nucleus regulates steroid response elements in promoters to modulate gene expression over a period of hours (7). Androgens and selective androgen receptor modulators are being explored as therapy for agerelated conditions, such as osteopenia and sarcopenia (8). In addition, androgens illicit rapid (occurring in minutes) nongenomic effects that may also have important biological effects in many tissues (5, 9 -11). The molecular mechanisms underlying these non-genomic actions are poorly understood. Several mechanisms have been proposed, including translocation of the steroid receptors to the cell surface membrane (12-14), nonspecific effects of steroids on the fluidity of lipids in the plasma membrane, direct allosteric modification of ligand-gated ion channels (5), and activation of G-protein coupled receptors (GPCRs) (9, 15, 16), including a putative pertussis toxin-sensitive GPCR (17-21). Identification of the putative GPCR that transduces the non-genomic effects of androgens may add significantly to our understanding of androgen biology that is relevant to normal human development and disease as well as the health risks of excessive pharmacological doses of anabolic steroids used in body building.GPRC6A is a pertussis toxin-sensitive member of the C family of GPCRs that senses amino acids, extracellular calcium, and osteocalcin (22-24). GPRC6A may function as an anabolic receptor coordinating the responses of multiple tissues to changes in nutrients and other factors (25). In this regard, ablation of this orphan G-protein coupled receptor leads to testicular feminization in male mice, suggesting that GPRC6A may also modulate sex steroid end organ responses (25).In the present study, we examined the role of GPRC6A in mediating the non-genomic effects of androgens on cell function in vitro and in vivo. We found that GPRC6A mediates the rapid signaling response to testostero...

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

GPRC6A Mediates the Non-genomic Effects of Steroids

Parrill

Quarles

2010

Journal of Biological Chemistry

169

143

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“…Importantly, inhibition of MAP kinase signaling was observed both in normal primary rat calvarial cultures and in a model of enhanced androgen responsiveness, AR-MC3T3 cells. This result contrasts with stimulation of MAP kinase signaling and AP-1 transactivation observed with brief androgen exposure, that may be mediated through non-genomic mechanisms (24,28,63). Since enhanced apoptosis is frequently associated with inhibition of MAP kinase signaling, the aim of the present study was to define the effects of androgen administration on osteoblast apoptosis in vitro and in vivo.…”

Section: Introductioncontrasting

confidence: 42%

“…In contrast, estrogen treatment had no direct effect on osteoclasts, whereas a similar indirect stimulation of osteoprotegerin was noted in osteoblasts [63 ].…”

Section: Updatementioning

confidence: 69%

Enhanced Androgen Signaling With Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

Wiren¹,

Jepsen²

2007

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) REPORT DATE (DD-MM-YYYY) 01-12-2005 REPORT TYPE Annual DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBEROregon Health and Science University Portland, OR 97239-0398 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTAndrogens have been shown to be important mediators of bone growth and remodeling independent of estrogen. A better understanding of the consequences of androgen action in bone is particularly important given increased anabolic steroid abuse. In addition, since bone architecture and bone material properties play important roles in stress fracture, analysis of this model represents a unique opportunity to characterize the consequences of androgen action in both genders on bone microarchitectural quality and the integrity of the skeleton in vivo. We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted to better understand the role of androgen signaling in bone. The central hypothesis of this proposal is that AR transactivation in the osteoblast lineage provides key regulatory signals that regulate the progression of osteoblast differentiation and osteogenesis, control the resorption of calcified bone, and modulate lineage determination in the marrow, to influence skeletal architecture and matrix quality. In the first year, we have successfully created the second line of AR-transgenic mice using the col2.3 promoter to drive AR expression. Ongoing analysis of studies (proposed in Specific Aim 1) suggest that AR transactivation (in young adults of col2.3 with col3.6 ARtransgenic animals) in mature osteoblasts is primarily responsible for mediating the effects of androgen on matrix quality and/or mineralization, while immature cells mediate effects of androgen on the periosteum and potentially body composition. Further, e...

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“…Recent studies have shown that rapid activation of cell signaling pathways (including pathways leading to p42/p44 ERK activation) is a fairly common response to steroids such as estrogen (59), progesterone (60), and androgen (61). Similarly, 1,25-D has rapid effects on the activity of cell signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

The Functional Consequences of Cross-talk between the Vitamin D Receptor and ERK Signaling Pathways Are Cell-specific

Narayanan

Sepúlveda

Falzon

et al. 2004

Journal of Biological Chemistry

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(8), and other cellular and physiological processes. Many of the actions of 1,25-D are mediated by an intracellular receptor, the vitamin D receptor (VDR), a member of the steroid/thyroid receptor superfamily of ligandregulated transcription factors (9, 10). The activity of VDR is dependent not only on the concentration of receptor and hormone but also on its heterodimer partner, retinoid X receptor (RXR), and the coactivator proteins that bind to the VDR and facilitate transcription of target genes (11).In addition to its actions as a modulator of transcription through activation of the VDR, 1,25-D can rapidly activate cell signaling cascades independent of a requirement for transcription (12-14). The means by which 1,25-D induces these changes has not been fully elucidated. Rapid activation of extracellular signal-regulated kinases, ERK1/ERK2 in NB4 promyelocytic leukemia cells can be induced not only by 1,25-D, but also by analogs that are unable to activate VDR, suggesting the possibility of a separate receptor (15). Antibodies to a membrane protein identified by Nemere et al. (16) block the ability of 1,25-D to induce rapid calcium uptake and activation of PKC in cartilage cells. VDRϪ/Ϫ osteoblasts take up calcium and activate PKC similar to the wild-type osteoblasts, implicating proteins other than VDR in these actions (17). In contrast, Gniadecki (18) has described activation of ERK through 1,25-D-induced activation of Raf as a result of interactions between VDR and the adaptor protein Shc. VDR-null osteoblasts do not exhibit ion channel responses in response to 1,25-D (13) and Erben et al. (14) have reported that deletion of the VDR DNA binding domain also eliminates non-genomic responses. Thus some of the rapid actions of 1,25-D may be dependent upon VDR, whereas others are not.Nuclear receptor family members including VDR and RXR as well as many of their coactivators, are phosphoproteins whose activities are also regulated by cell signaling pathways (19 -27). Thus 1,25-D can modulate VDR activity both through direct binding to VDR as well as by altering the kinase activities within the cell (9,11,12,28). Although VDR has not been reported to be a substrate for ERK, RXR␣ (one of the three RXR isoforms) (29) is phosphorylated by ERK, as are some of the VDR coactivators including SRC-1 (30).To better understand the functional interactions between VDR and the ERK signaling pathway, we sought to determine whether 1,25-D activates ERK in the osteoblastic cell lines, MG-63 and MC3T3-E1, and to evaluate the effects of ERK on VDR activity. We found that 1,25-D rapidly induced ERK activity and that this activation persisted at 24 h in both cell lines. Surprisingly, the effects of ERK activation on VDR activity in the two cell lines were very different. Overexpression of Raf-1 (an upstream activator of ERK) reduced VDR activity in MC3T3-E1 cells, but stimulated activity in MG-63 cells.

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Signaling Cross-talk from Gβ4 Subunit to Elk-1 in the Rapid Action of Androgens

Cited by 38 publications

References 66 publications

GPRC6A Mediates the Non-genomic Effects of Steroids

GPRC6A Mediates the Non-genomic Effects of Steroids

Enhanced Androgen Signaling With Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

The Functional Consequences of Cross-talk between the Vitamin D Receptor and ERK Signaling Pathways Are Cell-specific

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