MINIREVIEW
RNF13: anemergingRINGfingerubiquitinligase important
in cell proliferation
Xianglan Jin
1,2
, He Cheng
1
, Jie Chen
2
and Dahai Zhu
1
1 National Laboratory of Medical Molecular Biology, Tsinghua University, Beijing, China
2 Department of Pathology, Peking Union Medical College Hospital, Tsinghua University, Beijing, China
Introduction
The classic function of the 76-amino acid globular
polypeptide termed ubiquitin involves participation in
post-translational modification of proteins prior to
proteolytic degradation in the 26S proteasome com-
plex. The ubiquitinligase (E3) enzyme acts in concert
with appropriate ubiquitin-conjugating enzymes (E2)
and ubiquitin-activating enzymes (E1) to mediate
protein ubiquitination. It is now well recognized that
polyubiquitination of cellular proteins for proteasomal
degradation represents only one form of protein
modification. Apart from protein polyubiquitination,
mono-ubiquitination or multi-ubiquitination mediated
by E3 with appropriate lysine linkages have been
reported, and such patterns of protein ubiquitination
play important roles in regulating protein–protein
interactions in signal transduction, protein trafficking
between subcellular compartments and the biological
functions of proteins [1].
The ubiquitin ligases of eukaryotes fall into three
major families: RING, HECT and U-box proteins.
Based on genome-wide predictions, > 90% of ubiqu-
itin ligases are RING-type proteins including single-
subunit and SCF-like multiple-subunit E3 ligases [2].
RING finger protein 13 (RNF13) has been identified
Keywords
cancer; development; differentiation; E3
ubiquitin ligase; myogenesis; neurogenesis;
proliferation; RINGfinger domain; RNF13;
ubiquitination
Correspondence
D. Zhu, National Laboratory of Medical
Molecular Biology, Institute of Basic Medical
Sciences, Chinese Academy of Medical
Sciences & Peking Union Medical College,
Tsinghua University, 5 Dong Dan San Tiao,
Beijing 100005, China
Fax: +86 10 6510 5083
Tel: +86 10 6529 6949
E-mail: dhzhu@pumc.edu.cn or
dhzhusara@gmail.com
(Received 15 April 2010, revised 13
September 2010, accepted 12 October
2010)
doi:10.1111/j.1742-4658.2010.07925.x
Protein ubiquitination mediated by ubiquitin ligases plays a very important
role in a wide spectrum of biological processes including development and
disease pathogenesis. RINGfinger protein 13 (RNF13) is a recently identi-
fied ubiquitinligase which contains an N-terminal protease-associated
domain and a C-terminal RINGfinger domain separated by a transmem-
brane region. RNF13 is an evolutionarily conserved protein. Most interest-
ingly, RNF13 expression is developmentally regulated during myogenesis
and is upregulated in various human tumors. These data suggest that
RNF13, acting as anubiquitin ligase, might have profound biological func-
tions during development and disease. This minireview summarizes recent
work on RNF13 functions related to cell proliferation, differentiation and
cancer development.
Abbreviations
PA, protease-associated domain; RNF13, RINGfinger protein 13; TM, transmembrane.
78 FEBS Journal 278 (2011) 78–84 ª 2010 The Authors Journal compilation ª 2010 FEBS
as a novel RING-based ubiquitinligase and overex-
pression of the enzyme is apparent in various human
cancers, suggesting that RNF13 may play a significant
role in cancer development. Besides RNF13, eight
other related proteins have been reported to belong to
the Goliath family, including RNF128 (GRAIL),
RNF130, RNF133, RNF148, RNF149, RNF150,
RNF167 and RNF204 (Table 1) [2–4]. Alignments of
these nine proteins indicate high similarity in the prote-
ase-associated (PA), transmembrane (TM) and RING
domains (Fig. 1B). To date, GRAIL remains the best-
characterized member of this protein family, playing a
functional role in controlling the development of T-cell
clonal anergy.
RNF13: structure, expression, and
localization
The RNF13 gene is located at chromosome 3q25.1 in
human and is evolutionarily conserved in many meta-
zoans including the chimpanzee, dog, cow, chicken,
zebra fish, fruit fly, mosquito and Arabidopsis thaliana
(NCBI data). The full-length protein encoded by the
RNF13 gene is composed of 381 amino acid residues
(Accession Number NP_009213). RNF13 contains an
N-terminal PA domain and a C-terminal RING finger
domain separated by a TM region (Fig. 1A) [5,6]. The
PA domain is supposed to mediate substrate binding or
to be involved in protein–protein interactions [7–9].
The RING region is a C3H2C3 type and exerts E3
activity [5,6]. Bioinformatics predictions and experi-
mental evidence indicate that RNF13 is a type I TM
glycoprotein in which the PA domain faces the lumen
or extracellular region and the RING domain localizes
to the cytosol [5,6]. In addition, RNF13 also has a
PEST domain enriched in proline (P), glutamic acid
(E), serine (S) and threonine (T), and a nuclear localiza-
tion signal [6]. Together, these structural features imply
that RNF13 is a member of the Goliath family with
characteristics of PA-TM-RING domains [2–4,10].
Analysis of RNF13 gene expression shows that
RNF13 is ubiquitously expressed in various tissues of
chicken, mouse and human [5,6,11] (Fig. 2A). How-
ever, RNF13 expression is spatially regulated during
postnatal development in chicken. RNF13 is abun-
dantly expressed in skeletal muscle tissue at early
stages of embryonic myogenesis but its expression
gradually decreases during embryonic development
and becomes almost undetectable in skeletal muscle
tissue after hatching in chickens [11] (Fig. 2B). The
expression of RNF13 is greater in adult compared with
embryonic tissues in the mouse, especially in the liver
and brain [6]. More interestingly, RNF13 expression is
upregulated by tenascin and myostatin [11,12]. Myost-
atin is a member of the transforming growth factor-b
superfamily and functions as an inhibitor of muscle
cell proliferation and differentiation [13,14]. Tenascin
is an extracellular matrix glycoprotein and its expres-
sion is associated with cancer development [15]. There-
fore, it is conceivable that RNF13 may be involved in
controlling cell proliferation, and differentiation by
ubiquitination of proteins that play important regula-
tory roles in response to extracellular signals such as
myostatin and tenascin.
Based on bioinformatics predictions, the human
RNF13 protein may be encoded by two alternatively
Table 1. General information of the nine Goliath family members. ER, endoplasmic reticulum; INM, inner nuclear membrane; n ⁄ a, not avail-
able; TSSC5, tumor-suppressing subchromosomal transferable fragment cDNA; UE, ubiquitous expression; aa, amino acid.
Member Alias
Localization
of human
genome
Protein
size (aa)
mRNA
Accession No.
Expression
profile
E3
activity Substrates
Subcellular
localization Ref.
RNF13 c-RZF 3q25.1 381 NM_007282.4 UE Yes endosome,
INM ER ⁄ Golgi
[5,6,11,18]
RNF128 GRAIL,GREUL1 Xq22.3 428 NM_194463 UE, high in
kidney, liver
Yes RhoGDI, CD40L,
CD81, CD151,
CD83
Recycling
endosome
[7,8,42–44]
RNF130 Goliath 5q35.3 419 NM_018434 UE, high in
leukocytes,
liver
Yes Mitochondria [3,45]
RNF133 GREUL2 7q31.33 376 NM_139175 Testis specific Yes ER [46]
RNF148 GREUL3 7q31.33 305 NM_198085 n ⁄ an⁄ a
RNF149 GREUL4 2q11.2 400 NM_173647 n ⁄ an⁄ a
RNF150 GREUL5 4q31.21 438 XM_371709 n ⁄ an⁄ a
RNF167 RING105,
DKFZP566H073
17p13.2 350 NM_015528 UE, high in
kidney, liver
Yes TSSC5 Cytoplasmic
membrane
[47]
RNF204 Sperizin, ZNRF4 19p13.3 392 NM_181710.3 Testis specific n ⁄ a [48]
X. Jin et al. RNF13 and cell proliferation
FEBS Journal 278 (2011) 78–84 ª 2010 The Authors Journal compilation ª 2010 FEBS 79
spliced transcripts with the shorter transcript lacking
an exon in the 5¢ untranslated region (NCBI Accession
NM_007282.4 and NM_183381.2) [16]. A pseudogene,
also residing on chromosome 3, has been described
(NCBI Accession NM_007282.4 and NM_183381.2)
[16]. In addition, 15 alternatively spliced variants that
might encode 11 distinct RNF13 isoforms have been
annotated using the ace view program (http://
www.ncbi.nlm.nih.gov/IEB/Research/Acembly/) [17].
Structural analysis has revealed that RNF13 con-
tains a nuclear localization signaling domain and a
TM region [5,6]. Previous reports have provided
experimental evidence showing that RNF13 is a
nucleus- and ⁄ or membrane-associated protein. Data
from Tranque’s group indicate that RNF13 is present
in the nuclei of chicken embryonic heart tissue and
cultured embryonic cardiocytes [12]. Recently, Bocock
et al. [6] reported that RNF13 is present in the
endosomal–lysosomal system of COS cells, HeLa cells
and primary mouse neurons. We also showed that
RNF13 resides in the endoplasmic reticulum ⁄ Golgi
system of pancreatic cancer cells [5]. Very recently, an
intriguing study found that RNF13 is present on the
endosome membrane and is dynamically transported
A
B
Fig. 1. RNF13 protein domain structure and alignments of nine Goliath family members. (A) Schematic structure of RNF13 protein. SP,
signal peptide; PA, protease-associated domain; TM, transmembrane region; RING, RINGfinger domain; NLS, nuclear localization signal;
LC, low complexity [5,39]. LC region is shown according to
SMART [40,41]. (B) Alignments of nine Goliath family members.
RNF13 and cellproliferation X. Jin et al.
80 FEBS Journal 278 (2011) 78–84 ª 2010 The Authors Journal compilation ª 2010 FEBS
from multivescular endosomes to recycling endosomes
and inner nuclear membrane in response to 4b-phor-
bol 12-myristate 13-acetate stimulation [18]. It has
become evident that protein trafficking into the inner
nuclear membrane is animportant mechanism regulat-
ing gene expression, transducing signals from the
plasma membrane to the nucleus in response to vari-
ous stimuli. For example, amphiregulin and HB-EGF,
members of the epidermal growth factor family, are
both plasma membrane-anchored proteins, and partic-
ipate in transcriptional and epigenetic regulation of
target genes by traveling between the plasma mem-
brane and the inner nuclear membrane [19,20]. There-
fore, further investigation of the dynamic regulation
of RNF13 sublocalization within cells will shed light
on the functional roles of RNF13 as a membrane-
anchored E3 ubiquitinligase regulating gene expres-
sion by ubiquitination of nuclear proteins during
development and disease [21].
RNF13: functional roles
Work from the laboratory of Erickson and ours has
shown that RNF13 is a novel RING-containing E3
ligase [5,6] and that RNF13 expression is associated
with myogenesis, neuronal development and tumori-
genesis [5,6,11,22]. Emerging evidence suggests that the
ubiquitin ligase RNF13 plays critical roles in the regu-
lation of development and human disease.
Function of RNF13 in regulating
skeletal muscle growth and neuronal
development
We have recently shown that RNF13 is highly
expressed in proliferating myoblasts and its expression
gradually decreases during skeletal myogenesis. Inter-
estingly, our work has also demonstrated that RNF13
expression is upregulated by the muscle growth inhibi-
tor myostatin in chicken primary myoblasts and that
ectopic expression of RNF13 in vitro inhibits myoblast
proliferation with an E3 activity-dependent manner
[11]. Given that myostatin, as a cytokine, inhibits skel-
etal muscle proliferation and upregulates RNF13
expression in myoblast cells, it is very likely that
RNF13 may play animportant role in pathways
involved in myostatin signal transduction.
In addition, RNF13 is expressed in embryonic and
adult brain tissues [5,6,11,12], and overexpression of
RNF13 induces spontaneous neurite outgrowth in
PC12 cells [22]. Moreover, RNF13 presents an elevated
level in B35 neuroblastoma cells showing extension of
neurites after treatment with dibutyryl-cAMP [6].
Together, these results highlight the functional signifi-
cance of RNF13 in regulating skeletal muscle growth
and neuronal development. Therefore, identification of
RNF13 substrates is becoming a critical step in obtain-
ing a better molecular insight into RNF13 functions
during development.
RNF13 and cancer development
Ubiquitin ligases play critical roles in cancer develop-
ment and the well-studied enzymes are MDM2 and
SCF
Skp2
[23]. Elevated expression of MDM2 is appar-
ent in various tumors and is particularly associated
with late-stage and highly drug-resistant tumors [24].
A possible molecular role for MDM2, as a ubiquitin
ligase controlling tumor development, is degradation
of the tumor suppressor protein p53 by ubiquitination
[25,26]. Skp2, another ubiquitin ligase, is also overex-
pressed in human cancers and functions as an onco-
protein by regulating the stability of several tumor
suppressor proteins including p21, p57, p130 and
FOXO1 [27–31].
Recent studies have shown that RNF13 gene expres-
sion is associated with cancer development. Our labo-
ratory first reported a link between RNF13 expression
A
B
Fig. 2. Spatial and temporal expression patterns of RNF13.
(A) Western blot analysis of RNF13 protein in multiple human
tissues using anti-RNF13 IgG [5]. (B) Expression pattern analysis of
RNF13 during skeletal muscle development. The pectoralis muscles
of White Leghorn chickens were obtained from different develop-
mental stages (10-, 12-, 14-, 16- and 18-day embryos, as well as
from chicks 1 day and 1, 2, 3, 5 and 7 weeks after hatching). The
transcript and protein levels of RNF13 were determined by northern
and western analysis, respectively. The ethidium bromide staining
of 18S and 28S ribosomal RNAs and immunoblotting of tubulin
were used as equal loading controls [11].
X. Jin et al. RNF13 and cell proliferation
FEBS Journal 278 (2011) 78–84 ª 2010 The Authors Journal compilation ª 2010 FEBS 81
and pancreatic cancer progression by showing that
pancreatic ductal adenocarcinoma has high-level
expression of RNF13 (41.7% of 72 human samples)
and that such expression is related to histological grad-
ing [5]. Our data also revealed that RNF13 is present
in precancerous lesions including chronic pancreatitis
and pancreatic intraepithelial neoplasia, suggesting that
RNF13 is involved in inflammation-associated carcino-
genic change. Interestingly, Ralf et al. screened candi-
date genes, the expression of which is associated with
hepatocellular carcinoma in a mouse model, and iden-
tified RNF13 as one such gene [32]. Moreover, our
unpublished data from experiments with human tissue
microarrays also suggest an association between
RNF13 expression and human colon cancer develop-
ment, because higher levels of RNF13 protein are
detected in human colon cancer samples than in con-
trol samples. Most intriguingly, microarray analysis of
RNF13 gene expression in multiple tumor samples,
shown in Fig. 3 (F.M. Marincola, personal communi-
cation), indicates that RNF13 overexpression is com-
mon in various human tumors. Such expression is
much higher in renal cell carcinoma and esophageal
carcinoma cells compared with normal tissues respec-
tively. Similarly, RNF13 levels are elevated in several
other malignant tumors, including basal cell carci-
noma, melanoma and ovarian carcinoma using normal
peripheral blood mononuclear cell and immune cell
subsets as controls (Fig. 3). Based on the accumulating
observations, it seems that the ubiquitinligase RNF13
may be of profound significance in regulating tumori-
genesis in vivo.
More evidence implicating RNF13 in cancer devel-
opment has come from the observation of a close
relationship between RNF13 and tenascin C, an extra-
cellular matix molecule highly expressed in the stroma
of most solid tumors and linked to various features of
cancer including uncontrolled proliferation and metas-
tasis [5,33]. RNF13 expression is not only induced by
tenascin [12], but such expression also significantly
overlaps with tenascin C in pancreatic ductal adeno-
carcinoma samples [5]. Our recent studies have indi-
cated a functional role for RNF13 in regulating cell
proliferation and invasive growth in vitro [5,11], and
several other RING-type ubiquitin ligases have also
been reported to participate in cancer invasion and
metastasis. These enzymes include BCA2, Hakai and
HEI10 [34–38]. Therefore, a considerable body of
data provides significant information that lays the
groundwork for further experimental investigation of
RNF13 function involved in the regulation of cancer
development.
Perspectives
Recently, RNF13 has been identified as a novel E3
ubiquitin ligase and its expression patterns suggest that
RNF13 may exert profound biological functions
during development and the course of diseases includ-
ing myogenesis and tumorigenesis. However, the state
of current knowledge on RNF13 raises even more
questions. For example, how is expression of the
RNF13 gene regulated during development? What con-
trols the enzymatic activity of RNF13 ubiquitin ligase?
What is the biological significance of RNF13 traffick-
ing between subcellular compartments? What are the
actual functions of RNF13 in vivo and what molecular
mechanisms underlie its action? To answer these ques-
tions, the next crucial step is the generation of RNF13
transgenic ⁄ knockout mice and identification of its
substrates in vivo. In this manner, further molecular
and biochemical analysis of RNF13 functions in trans-
genic ⁄ knockout animals will greatly facilitate our
understanding of RNF13 actions during development
and human disease states such as cancer.
Acknowledgements
We thank Dr Francesco M Marincola (Department of
Transfusion Medicine, Clinical Center, National Insti-
tutes of Health) for sharing the unpublished data
shown in Fig. 2. We also thank Dr Yuchang Zhou
(Institute of Basic Medical Sciences, Chinese Academy
Fig. 3. Microarray analysis of RNF13 expression in several malig-
nant human tumors.
RNF13 and cellproliferation X. Jin et al.
82 FEBS Journal 278 (2011) 78–84 ª 2010 The Authors Journal compilation ª 2010 FEBS
of Medical Sciences) for valuable comments. This
work was supported by grants from the National Basic
Research Program of China (Nos. 2005CB522405,
2005CB522505, 2007CB946903, 2009CB 941602 and
2009CB825403), the National Natural Science Founda-
tion of China (Nos. 30721063 and 30471970), the
Chinese National Programs for High Technology
Research and Development (Nos. 2006AA10A121 and
2007AA02Z109), and the National Key Technology
R&D program (No. 2006BAI02A14).
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84 FEBS Journal 278 (2011) 78–84 ª 2010 The Authors Journal compilation ª 2010 FEBS
. MINIREVIEW
RNF13: an emerging RING finger ubiquitin ligase important
in cell proliferation
Xianglan Jin
1,2
, He Cheng
1
, Jie Chen
2
and Dahai. been
reported, and such patterns of protein ubiquitination
play important roles in regulating protein–protein
interactions in signal transduction, protein trafficking
between