| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* INSERM U716, Equipe AVENIR, Institut de Génétique Moléculaire, Paris; Université Paris 7, Paris, France;
Diseases of Aging Program, Ottawa Health Research Institute, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada; and
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
1Correspondence: Laboratoire de Pharmacologie Expérimentale et Clinique, INSERM U716/ Equipe AVENIR, Institut de Génétique Moléculaire, 27 rue Juliette Dodu, 75010 Paris, France. E-mail: majid.khatib{at}stlouis.inserm.fr
 |
ABSTRACT |
|---|
 TOP ABSTRACT BACKGROUNDPHENOTYPES OF PROPROTEIN...PHENOTYPES OF INHIBITORS OF...SUMMARY AND CONCLUDING REMARKSREFERENCES |
|---|
Key Words: abnormal embryonic development • hormonal disorder • cellular proliferation • infertility • dyslipidemias • human patients
|
BACKGROUND |
|---|
|
TOPABSTRACTBACKGROUNDPHENOTYPES OF PROPROTEIN...PHENOTYPES OF INHIBITORS OF...SUMMARY AND CONCLUDING REMARKSREFERENCES |
|---|
2
3
4
5)
. The PCs are implicated in the processing of multiple protein precursors, including proteases, growth factors, and receptors at multibasic recognition sites exhibiting the general motif (K/R)-(X)n-(K/R)
, where X is any aa except Cys and n = 0, 2, 4, or 6. The enzyme SKI-1 recognizes the motif (R/K)-X-(L, I, V)-Z, where Z is any aa except Pro, Cys, Glu, and Val. Although no substrate is yet known for PCSK9, this convertase autocatalytically cleaves its prosegment at the motif VFAQSIP, with Val at P4 being the most critical residue (6)
.
PCs have been linked recently to various pathologies such Alzheimer’s disease, tumorigenesis, and infections. In Alzheimer’s disease, furin and PC5/6 were found to process the zymogens of both 
- and ß-secretases, the latter being involved in the generation of amyloid-ß (Aß), the principal component of senile plaques, thereby implicating directly the PCs in this neurodegenerative disease (7
, 8)
. The participation of the convertases in tumor progression was deduced from the dramatic changes in several phenotypes that affect the metastatic potential of various tumor cells after the inhibition of PC activity in these cells (9
10
11
12
13)
. In parallel, overexpression of the convertases enhanced tumorigenesis and aggressiveness of tumor cells via augmented processing and activation of various molecules involved in tumorigenesis and metastasis (9
10
11
12
13)
. These include metalloproteases, adhesion molecules, growth factors, and growth factor receptors (9
10
11
12
13)
. The implication of the PCs in various bacterial toxins activation and viral infection is also well documented (14
15
16
17
18
19)
. Various bacterial toxins are produced as inactive, unprocessed forms that are activated by the PCs, e.g., Diptheria toxin, Pseudomonas aeruginosa exotoxin A (PEA), Botulinum neurotoxin, Bordetella dermonecrotic toxin, and pore-forming toxins such as the aerolysin (14)
. Similarly, acquisition of the infectious capacity and/or cell-cell spread of various viruses requires the processing of their surface glycoproteins by the PCs. These include HIV-1, Hong Kong influenza virus, Ebola virus, and the severe acute respiratory syndrome coronavirus (15
16
17
18)
. Inhibition of processing of some of these viral surface glycoproteins by the PC inhibitors completely abrogated the virus-induced cellular cytopathicity (17
, 19)
.
To determine the physiological importance of the convertases, their corresponding genes were disrupted individually using complete or conditional approaches. The varieties in the PC knockout phenotypes or PC inhibitor knockout (KO) phenotypes resulting from the absence of functional convertases or endogenous convertase inhibitors/modulators emphasize the complexity and wide array of the protein precursors that are processed by these enzymes (Fig. 1
). Some of the PCs protein precursors may be processed by one or more specific convertases. Based on the observed phenotypes of the PC null mice, it became apparent that some precursors are processed by a specific convertase at specific stages of embryonic development. To date, the information gathered from the available PC null mice revealed that only the absence or dysfunction of furin, PC5/6, and SKI-1/S1P is lethal at early embryonic stages. KO mice of PC1/3 (PCSK1), PC2 (PCSK2) genes are viable despite the manifestation of hormonal and/or neuroendocrine deficiency. PC4 null mice are infertile or subfertile. PACE4 null mice are 75% viable and some exhibit craniofacial abnormalities. Tissue-specific conditional KO allowed the analysis of the function of some PCs in these tissues. Thus, liver-specific conditional SKI-1/S1P null mice exhibit disorganized lipid and fatty acid homeostasis due to the lack of SREBP-1 and SREBP-2 processing, and PCSK9 knockout mice show enhanced cholesterol uptake by the liver LDLR. Only mice with disrupted PC7 gene (PCSK7) failed to show any apparent abnormal phenotype (Fig. 1)
.
|
|
PHENOTYPES OF PROPROTEIN CONVERTASES NULL MICE |
|---|
|
TOPABSTRACTBACKGROUNDPHENOTYPES OF PROPROTEIN...PHENOTYPES OF INHIBITORS OF...SUMMARY AND CONCLUDING REMARKSREFERENCES |
|---|
, 21)
. Inactivation of the fur locus by homologous recombination in mouse causes embryonic death shortly after e10.5 due to hemodynamic insufficiency and cardiac ventral closure defects (21)
. The mutant embryos failed to develop large vessels despite the presence of endothelial cell precursors (Fig. 2
). While the specific physiological substrates of furin in the embryonic cardiovascular system have not yet been identified, the striking overlap in the distribution of furin mRNA coincided with that of several molecules reported to play crucial roles during this developmental stage. Among these molecules, members of the transforming growth factor (TGF) ß family, such as TGFß1 (22)
, were recently shown to be efficiently processed by furin (23)
. A phenotype similar to furin null mice was also observed in embryos deficient in TGF-ß1 (22
, 24)
. This suggests that lack of processing and activation of this growth factor, or possibly other precursors involved in the early cardiac development, could be responsible for the defects observed in furin null embryos.
|
In addition to these cardiovascular defects, the chorion of the furin null embryos fails to fuse with the allantois that becomes highly vacuolated at 
e9.5 (Fig. 2)
. Similar absence of chorioallantoic fusion had been observed in embryos lacking bone morphogenetic protein 5 (BMP5) and BMP7 (25)
, vascular cell adhesion molecule (VCAM-1), or 4-integrin (26
, 27)
. VCAM-1 and 4-integrin are two cell surface adhesion molecules that were reported to bind each other and are required for cell-cell adhesion (28)
. The fact that furin has recently been shown to mediate the processing of various integrins, including 4ß1 (29)
, suggests the importance of this convertase in the generation of fully processed 4ß1, a step probably required in the interaction between active 4ß1 and VCAM-1 during embryonic development. In addition, it was speculated that furin is required for the induction of the expression of various adhesion molecules, including VCAM-1 (9)
. The most damaging deficiency in the furin mutant embryos is their failure to undertake ventral closure in order to form a looping heart tube and a coherent primitive gut (21)
(Fig. 2)
. Such a mechanism requires cellular proliferation and migration (Fig. 1)
, both of which are regulated by furin (9)
. In addition, these mice were unable to undergo axial rotation (21)
. This process is usually preceded by the rightward looping of the heart tube, suggesting the crucial role of furin in the ventral closure and axial rotation during embryonic development.
PC2 and PC1/3 knockout mice
Unlike furin KO mice, PC2 null mice are viable (30)
. The latter were generated by introducing the neomycin resistance gene (Neor) into the third exon of the mouse PC2 gene. This gene insertion prevents PC2 from undergoing autoactivation and secretion (30)
. Although PC2 mutant mice appear normal at birth they exhibit retarded growth. Analysis of these mice reveals chronic fasting hypoglycemia and a deficiency in circulating glucagon. These phenotypes are consistent with previous reports on the role of PC2 in the conversion of proinsulin and proglucagon (31)
. Processing of prosomatostatin is also severely impaired in these mice. In adult mutant mice, the islets showed marked hyperplasia of alpha and delta cells and a relative diminution of beta cells (Fig. 3
). Since PC2 is known to process various neuroendocrine precursors, many of these molecules were found not to be fully processed in PC2 null mice, among them neuronal proCCK (32)
, neurotensin, neuromedin N (33)
, prodynorphin (34)
, proorphanin FQ/nociceptin, and proopiomelanocortin (POMC) -derived peptides (35)
. These findings indicate that PC2 is not required for normal embryonic development but controls the maturation of multiple regulatory peptides or precursor proteins. PC2 is believed to be a major endoproteolytic processing enzyme of the regulated secretory pathway and is expressed solely in neural and endocrine cells throughout the brain and endocrine system.
|
Contrary to PC2, PC1/3 gene disruption results in severe developmental abnormalities. The PC1/3 null mice exhibit growth retardation. The adult mutant mice are 60% of the normal size and phenotypically resemble mice that have mutant growth hormone-releasing hormone (GHRH) receptor (Fig. 4
) (36)
. Insulin growth factor 1 (insulin-like growth factor-1) and GHRH levels were significantly reduced along with pituitary GH mRNA levels (Fig. 4)
, suggesting that this reduction contributes to the growth retardation observed in these mice (36
, 37)
. Evaluation of GHRH precursor levels and its active forms revealed the accumulation of the unprocessed form that was associated with low or undetectable mature GHRH. Similarly, analysis of several protein precursors known to be processed by PC1/3 revealed that these mice, like PC2 mutant mice, exhibit multiple defects in other hormone precursor processing events. These include the hypothalamic GHRH, pituitary POMC, proinsulin, and intestinal proglucagon (38)
. In contrast to PC2 null mice, PC1/3 null mice process normally pituitary POMC to ACTH and have normal levels of blood corticosterone. Like PC2 null mice, they also developed hyperproinsulinemia. These mice maintain normal glucose (Glc) tolerance in response to i.p. injection of Glc, suggesting that their hyperproinsulinemia does not impair their Glc homeostasis (38
, 39)
.
|
Previously, Jackson et al. (39)
reported a case of PC1/3 deficiency in a human subject who was a compound heterozygous for a splicing mutation leading to a truncated protein and nonsynonymous mutation leading to G483R change in the encoded protein. The latter mutation prevents the processing and secretion of proPC1/3 from the endoplasmic reticulum. The female patient showed neonatal obesity and abnormal Glc homeostasis. Further analysis revealed that she was completely unable to process normal proinsulin to insulin with fasting normoglycemia. Subsequent studies revealed the presence of other endocrine defects, including the presence of very high circulating levels of proinsulin and multiple forms of partially processed POMC [intermediate ACTH precursors], low-serum estradiol, follicle-stimulating hormone, and LH (39)
. In 2003, another PC1/3 deficiency female subject was reported (40)
. In addition to the shared phenotypes with the previous subject, this female infant presented severe diarrhea, which started on the third postnatal day. Metabolic studies revealed a defect in the absorption of monosaccharides and fat, revealing the role of PC1/3 in the small intestinal absorptive function (40)
. Although the phenotypes of the PC1/3 null mice differ from those observed in these patients (PC1/3 null mice are not obese), the findings confirmed the importance of PC1/3 as a key neuroendocrine convertase.
PACE4 knockout mice
Like furin, PACE4 is critical for normal embryonic development, particularly during the specification of left-right axes and anterior central nervous system (CNS) development. In the absence of PACE4, embryos develop specific defects and/or display complex craniofacial malformations, a phenotype that is not completely penetrant compared with the furin-KO mice phenotype (Fig. 5
) (41)
. This suggests that although PACE4 and furin share the ability to process similar substrates, they may also process one or more different substrates during the processes of embryonic development. The specification of both the anteroposterior and left-right axes has been shown to depend on TGFß-related signaling molecules, including Nodal, Lefty, and BMPs (42
, 43)
. Some of these proteins were shown to be endoproteolyticaly processed by the basic aa-specific PCs (23)
. Nodal activities involved in the organization and patterning of the primitive ectoderm are required for anteroposterior axis formation (44
, 45)
, whereas at late streak stages nodal expressed asymmetrically in the mesoderm mediates positional information, specifying the left side of the embryo (46)
. In addition to nodal, TGF-related molecules such as Lefty1 and Lefty2 were reported to participate actively in these processes by antagonizing TGF-ß-related protein effects (44)
.
|
Previously, disruption of the asymmetric expression of these TGF-related genes was shown to affect the situs of the body and isomerisms of the organs in mice (42
, 43
, 46)
. It was postulated that during left-right axis formation, PACE4 may activate a signaling pathway, such as BMP, which in turn inhibits the symmetric nodal expression and induces Lefty1 expression, which then represses nodal and Lefty2 (41
, 47)
. Accordingly, in PACE4 mutant mice, the Lefty2 mRNA was abundant in the midline, showing bilateral expression (41)
. Thus, the symmetric expression of nodal seems to be related to impaired BMP processing (41)
. Based on these studies, PACE4 seems to be required to maintain the balance between growth factors and their receptors and their antagonistic proteins in order to ensure the specification of the left-right axes.
PC4 knockout mice
Due to the predominant expression of PC4 in the testis, it was anticipated that disruption of the PC4 gene might affect the fertility of PC4 mull mice. Microscopic analysis of the seminiferous epithelium derived from these mice revealed that the number of spermatogonia, spermatocytes, spermatids, as well as motility parameters of spermatozoa, was similar to those of normal mice (Fig. 6
) (48)
; however, the percentage of hyperactivated spermatozoa was reduced in the PC4 null mice (Fig. 6)
. Earlier it was shown that hyperactivation is a qualitative change in sperm motility that facilitates sperm penetration of oocyte vestments, a critical step in fertilization (49)
. These observations suggest that PC4 null mice are infertile because of the inefficiency of their spermatozoa during oocyte dissemination. Testing the fertilizing ability of PC4 null sperm, Mbikay et al. observed that both the rates of fertilization and the percent of fertilized eggs developing to the blastocyst stage were reduced (48)
. These data suggest that PC4 could influence reproduction by processing precursor proteins required for normal fertility.
|
Many PC substrates are expressed in testicular germ cells. These include precursors to pituitary adenylate cyclase-activating peptide (PACAP) (50)
, GHRH-related peptides (51)
, enkephalins, nerve growth factors (52)
, fertilins (53)
, insulin-like growth factor (IGF) -1, TGF, and others (54
55
56)
. Of these, some were shown to be important in reproduction, such as fertilins, IGF-1, and TGF-ß (55
, 56)
. The only precursor known not to be processed in the testis and the ovaries of PC4 null mice is pro-PACAP (57)
. How impaired processing of this and other substrates in testicular germ cells and in sperm causes infertility remains to be investigated.
Knockout mice of PC5/6 and PC7
In 2003, very preliminary observations were mentioned by the group of A. Franzusoff regarding mice where the isoform PC5/6B was knocked out (for a review, see ref. 56
). The authors found that, like furin, the expression of PC5/6 in embryos is highest at day e7.5–8.5 in some tissues, including the amnion, the extraembryonic endoderm, and the mesoderm. They briefly mentioned that inactivation of the PC5/6-B isoform expression resulted in embryonic lethality. However, no data were presented (56)
. Using in situ hybridization and/or quantitative polymerase chain reaction, we recently extensively documented the tissue distribution of PC5/6 during development and in adulthood, as well as in various cell lines (58)
. At e9.5, PC5/6 seems to be already expressed in the somites, bulb of umbilical cord, and lung bud. At e10.5–11.5, the first bronchial arch, the wall of bulbus cordis, and the nasal pit were also labeled. By e15.5 the PC5/6 pattern of expression becomes similar to that of the adult, with strong labeling in small intestine, kidney, and lung (58)
. We also showed that the isoform PC5/6-A is the predominant form in most adult mouse tissues except for the intestine and kidney, where PC5/6-B predominates (58)
. Recently, we demonstrated that PC5/6-A and PACE4 probably exert their proteolytic action at the cell surface/extracellular matrix, as they are retained at the plasma membrane as a complex with tissue inhibitors of metalloproteases (TIMPs) and heparan sulfate proteoglycans (59)
. To investigate the physiological roles of PC5/6, we generated a mouse Pcsk5
4-deficient allele missing exon 4 that encodes the catalytic Asp173. We found that while the 4/+ heterozygotes were healthy and fertile; the 4/4 embryos died between embryonic days 4.5 and 7.5 (58)
. Previously PC5/6 was reported to be involved in the activation of various molecules required for the normal embryonic development such as platelet-derived growth factors (PDGFs), BMPs, and particularly lefty proteins (60
, 61)
. Although the possible presence of these important proteins as inactive forms during the processes of embryonic development in PC5/6 null mice may explain the death of these mice during their early embryonic stage of development, further studies are required for identification of the specific substrates of PC5/6 whose processing is crucial for normal embryonic development. The characterization of such substrates will help to unravel the actual physiological roles of PC5/6. Finally, the use of tissue-specific conditional knockout strategies should allow us to delineate the physiological functions of PC5/6 in various tissues.
Different from the other PC null mice, PC7 null mice embryos show no apparent abnormal phenotype (61)
. This may be explained by the fact that PC7 expression overlaps extensively with that of furin. Many reports show that PC7 and furin process the same substrates, such as platelet-derived growth factor (PDGF) -AA (12)
, PDGF-BB (62)
, vascular endothelial growth factor (VEGF) -C (13)
, BMP (60)
, and others. This suggests a pivotal role for furin, but not for PC7, in processing of these substrates in the adult. Alternatively, the most conserved convertase PC7 may be involved in the processing of a panel of nonessential substrates. Double KOs of furin and PC7 may help resolve the issue of the possible critical functions of PC7 during embryogenesis in a furin null background.
Proprotein convertases that process substrates at nonbasic residues
SKI-1/S1P and PCSK9 genes disruption
SKI-1/S1P substrates known to date include sterol-regulated element binding proteins (SREBPs), the brain-derived neurotrophic factor (BDNF), ATF-6, somatostatin, some CREB-like proteins and a few viral glycoproteins (4
, 64
65
66
67
68)
. Based on its ability to process and activate the lipogenic transcription factor SREBPs, it was anticipated that the lack of SKI-1/S1P activity would induce a defect in the lipid homeostasis in SKI-1/S1P null mice (67)
. Previously, SREBPs were shown to play a key role in the fundamental feedback mechanism of cellular lipid homeostasis. The transcriptional activation of genes containing sterol responsive element (SRE) is known to be regulated by sterols through modulation of the proteolytic maturation of SREBPs (4
, 64
65
66)
. Although the use of the Cre recombinase system failed to induce complete disruption of SKI-1/S1P in liver, partial disruption of SKI-1/S1P caused a reduction in the rates of cholesterol and fatty acids synthesis (68)
. Further analysis revealed that the level of the nuclear SREBPs and their target genes for fatty acid synthase, density lipoprotein (LDL), and LDL receptor all declined (68)
. The incomplete and partial nature of these declines suggested that the disruption of SKI-1/S1P by inducible Cre recombinase system was not sufficient to abolish SKI-1/S1P functions or, alternatively, that another protease substituted for SKI-1/S1P in the liver of these mice. Although the role of SKI-1/S1P in the homeostasis of cholesterol and fatty acids is now well established, this enzyme also seems to be involved in the morphology of cartilage. Indeed, analysis of the zebrafish mutant, gonzo, which has defects in cartilage formation as revealed by the irregular chondrocyte morphology, indicated the involvement of the mutated SKI-1 in the gonzo phenotype (69)
. Accordingly, this observation was confirmed by phosphomorpholino knockdown that encodes zebrafish SKI-1 (69)
. As for SKI-1/S1P liver null mice, gonzo fish present also abnormal distribution of lipids, however, knockdown of SREBP cleavage-activating protein (SCAP), which forms a complex with sterol regulatory element binding proteins (SREBP) and is essential for SKI-1/S1P cleavage, results only in lipid phenotypes, and the cartilage remains normal, suggesting that the defects in gonzo cartilage are independent of the lipid defect (69)
.
Abifidel et al. recently reported that members of several families with a high risk for coronary heart disease due to increased levels of the LDL, exhibit a mutation in the PCSK9 gene (encoding proprotein convertase subtilisin/kexin type 9) (70)
that was previously identified by our group (5)
, suggesting a possible role for this convertase in cholesterol homeostasis and its implication in a dominant form of familial hypercholesterolemia FH3 (70)
. Like SKI-1/S1P, PCSK9/NARC-1 is expressed mainly in the liver and small intestine, two organs involved in cholesterol homeostasis. Recently; complete knockout of PCSK9 was achieved and the animals showed a 50% reduction in circulating LDL cholesterol (71)
. Administration of HMG-coenzyme A reductase inhibitors known as "statins" resulted in a further 50% reduction of their circulating LDL levels, opening the way to new pharmacological drugs combining the effects of statins and a PCSK9 inhibitor/silencer (72)
. Finally, recent articles clearly demonstrated the importance of PCSK9 in regulating the levels of circulating LDL cholesterol in the human population, whereupon certain mutations are directly associated with the development of hypercholesterolemia with a gain of function of PCSK9, while others implicate a loss of function and result in a hypocholesterolemia phenotype (72)
. This clearly paves the way toward a mechanism-based treatment of dyslipidemias using PCSK9 inhibitors or silencers in combination with statins.
|
PHENOTYPES OF INHIBITORS OF PROPROTEIN CONVERTASES |
|---|
|
TOPABSTRACTBACKGROUNDPHENOTYPES OF PROPROTEIN...PHENOTYPES OF INHIBITORS OF...SUMMARY AND CONCLUDING REMARKSREFERENCES |
|---|
, 74)
and 7B2 (74)
, respectively. ProSAAS null mice are not yet available whereas, like PC2 null mice, 7B2 null mice completely lack PC2 activity and have severely reduced levels of bioactive peptides, such as mature enkephalins and glucagon, known to be synthesized by PC2-specific mechanisms (34
, 76)
. Recent analysis of the processing of proCCK in brain extracts from PC2 and 7B2 null mice revealed the presence of an exaggerated increase of cerebral proCCK and reduced cholecystokinin (CCK) active form, confirming the importance of the complex PC2/7B2 in the processing and activation of several protein precursors. In contrast, recent comparative studies between the PC2 and 7B2 null mice revealed that the loss of 7B2, but not of PC2, resulted in the alteration of dopaminergic sensitivity in the intermediate lobe of the pituitary, hypersecretion of ACTH from this lobe, hypercortisterolemia, a Cushing-like syndrome, and peripubertal death. After adrenalectomy, 7B2 null mice survived and exhibited normal levels of pituitary dopamine, circulating ACTH, and corticosterone, but developed severe obesity (77)
. |
SUMMARY AND CONCLUDING REMARKS |
|---|
|
TOPABSTRACTBACKGROUNDPHENOTYPES OF PROPROTEIN...PHENOTYPES OF INHIBITORS OF...SUMMARY AND CONCLUDING REMARKSREFERENCES |
|---|
) revealed the complexity and wide array of the protein precursors that are processed by these enzymes. The ability of the basic aa-specific PCs to process in vitro many protein precursors exhibiting the general motif (K/R)-(X)n-(K/R) raises many questions about the divergence in the KO phenotypes of these enzymes (Table 1)
. It seems that during embryogenesis the individual PCs may not be redundant in function and may indeed be limiting in some tissues. In adults however, redundancy may be more prevalent in some, but surely not all tissues. Thus, the conditional furin KO in liver did not decrease extensively the processing of precursors previously thought to be processed best by this convertase (78)
, suggesting the redundant action of other convertases in hepatocytes. Whether this type of redundancy will apply to all tissues is doubtful, although definitive data are not yet in. The most enigmatic situation is the PC7 null mice embryos that show no apparent abnormal phenotype or any phenotype in older animals, and yet PC7 is the most conserved basic aa-specific convertase that was shown to be able to process various substrates with the same efficiency as the other PCs. While studies of the PC null mice confirm the crucial role of these enzymes in the activation of proteins involved in physiological processes, there is also growing evidence of their role in various pathologies. Some PCs have been reported to be involved in Alzheimer’s disease, rheumatoid arthritis, cancer, dyslipidemias, and other diseases. Therefore, the control of PC expression and/or activity is expected to provide potentially novel mechanism-based therapeutic approaches toward disease-management.
|
|
ACKNOWLEDGMENTS |
|---|
Received for publication February 8, 2006. Accepted for publication May 15, 2006.
|
REFERENCES |
|---|
|
TOPABSTRACTBACKGROUNDPHENOTYPES OF PROPROTEIN...PHENOTYPES OF INHIBITORS OF...SUMMARY AND CONCLUDING REMARKSREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  R. Essalmani, A. Zaid, J. Marcinkiewicz, A. Chamberland, A. Pasquato, N. G. Seidah, and A. Prat In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate PNAS, April 15, 2008; 105(15): 5750 - 5755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Anderson, A. L. Goldberg, and M. Whitman Identification of a Novel Pool of Extracellular Pro-myostatin in Skeletal Muscle J. Biol. Chem., March 14, 2008; 283(11): 7027 - 7035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J Diaz, K. Sugiura, and J. J Eppig Regulation of Pcsk6 Expression During the Preantra |
