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doi:10.1111/j.1745-7270.2008.00442.x |
Mechanisms of action of angiogenin
Xiangwei Gao and Zhengping Xu*
Research Center for Environmental Genomics,
and Bioelectromagnetics Laboratory, Zhejiang University School of Medicine,
Hangzhou 310058, China
Received: May 13,
2008
Accepted: June 10,
2008
This work was
supported by grants from the National Natural Science Foundation of China
(30171035, 30470670 and 30770470), the Program for New Century Excellent
Talents in University (No. NCET-05-0521) and the Zhejiang Provincial Program
for the Cultivation of High-level Innovative Health Talents (2007-191)
*Corresponding
author: Tel, 86-571-88208164; Fax, 86-571-88208163; E-mail, [email protected]
Angiogenin induces angiogenesis by activating
vessel endothelial and smooth muscle cells and triggering a number of
biological processes, including cell migration, invasion, proliferation, and
formation of tubular structures. It has been reported that angiogenin plays its
functions mainly through four pathways: (1) exerting its ribonucleolytic
activity; (2) binding to membrane actin and then inducing basement membrane
degradation; (3) binding to a putative 170-kDa protein and subsequently
transducing signal into cytoplasm; and (4) translocating into the nucleus of
target cells directly and then enhancing ribosomal RNA transcription.
Angiogenin can also translocate into the nucleus of cancer cells and induces
the corresponding cell proliferation. Furthermore, angiogenin has
neuroprotective activities in the central nervous system and the loss of its
function may be related to amyotrophic lateral sclerosis. This review intends
to conclude the mechanisms underlying these actions of angiogenin and give a
perspective on future research.
Keywords angiogenin; angiogenesis; cancer; amyotrophic lateral sclerosis
Angiogenin (ANG) was originally isolated from the conditioned medium
of cultured HT-29 human colon adenocarcinoma cells based solely on its
angiogenic activity [1]. The gene encoding ANG is present as a single copy per
haploid genome, and localizes on chromosome 14q11 [2]. The mature ANG is a
basic, single-chain protein containing 123 amino acids with a molecular weight
of about 14,400 Da [1], and is a homolog of bovine pancreatic ribonuclease A.
Although its ribonucleolytic activity is rather weak, it is essential for
angiogenesis and other functions. ANG has also been reported to induce the
proliferation of cancer cells directly. Recently, ANG gene was
identified to be a potential amyotrophic lateral sclerosis (ALS) related gene.
In this review, we will overview the functions and mechanisms of ANG in these
physiological and pathological processes.
Functions and Mechanisms of ANG in
Angiogenesis
Angiogenesis, the process of new blood-vessel growth, plays an
essential role in normal physiological processes, such as development and
reproduction. However, pathological angiogenesis occurs in many
angiogenesis-dependent diseases such as tumors and other non-neoplastic
diseases [3]. As a key angiogenic factor, ANG is believed to be an ideal target
for anti-angiogenesis therapy. Therefore, revealing the mechanism of action of
ANG will facilitate not only the understanding of angiogenesis, but also the
discovery of angiogenesis inhibitors.
It has been reported that ANG interacts with endothelial and smooth
muscle cells to induce a wide range of cellular responses including cell
migration, invasion, proliferation, and formation of tubular structures. Four
aspects of ANG have been discovered to be necessary for the process of
ANG-induced angiogenesis, including ribonuclease activity, basement membrane
degradation, signaling transduction, and nuclear translocation.
ANG exerts its ribonucleolytic activity
ANG belongs to the ribonuclease superfamily with a 33% sequence
homology to the pancreatic ribonuclease A [4]. Although the crystal structures
of human ANG and pancreatic ribonuclease A have high similarity, there is
notable difference in the ribonucleolytic active center. The pyrimidine binding
site of ANG is “obstructed” by the glutamine (Gln)117 residue, which results in
a very weak ribonucleolytic activity, about 105–106 lower
than that of RNase A. Movement of Gln117 and the adjacent residues may be
required prior to or during catalysis for substrate binding to ANG [5]. Latter
experiments showed that mutation of this residue greatly increased the RNase
activity of ANG but without changing its specificity, which further supported
the notion that Gln117 impeded the ribonucleolytic activity of ANG [6].
Although weak, the RNase activity is necessary for the functions of ANG.
Mutations of His13, Lys40, or His114, key amino acids for the RNase activity of
ANG, greatly decrease its angiogenic activity in the chick embryo
chorioallantoic membrane (CAM) assay [7,8]. Moreover, human placental
ribonuclease inhibitor (PRI) [9] and compound 65828 [10] targeting the ANG
enzymatic active site abolish both the ribonucleolytic activity and the
angiogenic activity of ANG.
ANG stimulates basement membrane degradation
Besides its ribonucleolytic activity, the binding of ANG with
endothelial cell surface is also needed for its biological functions, and amino
acid residues from 60 to 68 are critical in this process [11]. During an effort
to identify the ANG receptor in endothelial cells, a 42-kDa cell surface
protein was initially found as an ANG-binding molecule [12], and was later
shown to be a smooth muscle type a-actin [13]. The cell surface actin seems to
be involved in the basement membrane degradation. Upon binding of ANG to actin,
some of the ANG-actin complexs dissociate from the cell surface. Thereafter,
this complex accelerates tissue-type plasminogen activator (tPA)-catalyzed
generation of plasmin from plasminogen [14]. Therefore, through the formation
of its actin complex, ANG promotes the degradation of basement membrane and
extracellular matrix and thus allows endothelial cells to penetrate and migrate
into the perivascular tissue [15], an essential feature of angiogenesis (Fig.
1).
ANG activates signaling transduction
Because actin is not an ANG receptor for signal transduction, a
170-kDa molecule was later identified as a potential ANG receptor located on
the endothelial cell surface, and expressed only on ANG-responsive but sparsely
cultured endothelial cells (<2×104 cells/cm2) [16]. Unfortunately, the nature of this molecule is still elusive.
Although there is a lack of knowledge on ANG receptors, several
pathways have been proposed to be activated by ANG stimulation. In response to
ANG treatment, extracellular signal-related kinase1/2 (ERK1/2) [17] as well as
protein kinase B/Akt [18] were activated in human umbilical vein endothelial
(HUVE) cells, and phosphorylation of stress-associated protein kinase/c-Jun
N-terminal kinase (SAPK/JNK) was observed in human umbilical artery smooth
muscle (HuASM) cells [19] (Fig. 1). Activations of these signaling
pathways by ANG are considered to be an important mechanism leading to cell
proliferation and further angiogenesis.
It appears that the 170-kDa putative receptor and actin are not
expressed concurrently on the endothelial cell surface. They seem to be
expressed under different cell conditions and play roles at different
stages of ANG-induced angiogenesis. In subconfluent cells, actin is
expressed and binds to ANG specifically [13]. Binding of ANG to cell
surface actin results in activation of a cell-associated protease system
that promotes cell invasion [14]. After the cells start to migrate and invade
into the basement membrane, the local density of the cells in the vicinity
of the migrating cells decreases, thus triggering the expression of the
170-kDa putative ANG receptor on the remaining adjacent cells. These
cells become responsive to stimulation of ANG and will therefore divide to
fill the space created by the migrating cells. The expression of the
receptor may then be turned off when the cell density increases. It
is speculated that such density-dependent receptor expressions may regulate
the ANG-induced growth of the new capillary network.
ANG undergoes nuclear translocation and enhances rRNA transcription
Angiogenin undergoes nuclear translocation in endothelial cells and
smooth muscle cells [19], which has also been shown to be necessary for
ANG-induced angiogenesis (Fig. 1). Inhibition of nuclear translocation
of ANG [20] or mutagenesis of its nuclear localization sequence [21] both
abolish its angiogenic activity. Nuclear translocation of ANG in endothelial
cells is rapid [22], but is strictly dependent on cell density [22]. It
decreases as cell density increases and ceases when cells are confluent.
The nuclear function of ANG has been found to enhance ribosomal RNA
(rRNA) transcription [23] (Fig. 1). An ANG-binding element (ABE), known
as CTCT repeats, has been identified from the intergenic spacer (IGS) region of
rDNA. ABE binds ANG specifically and exhibits ANG-dependent promoter
activity in the luciferase reporter system [24]. Now it is recognized that the
nuclear ANG assumes an essential role in endothelial cell proliferation and is
necessary for angiogenesis induced by other angiogenic factors, such as acidic
fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and
vascular endothelial growth factor (VEGF) [25]. ANG-stimulated rRNA transcription
in endothelial cells has been shown to serve as a crossroad in the process of
angiogenesis induced by the other angiogenic factors.
However, the process of nuclear translocation of ANG is largely
unknown. The first step required for the nuclear translocation of exogenous ANG
is the internalization of the protein, and receptor-mediated endocytosis seems
to be involved in the internalization [21]. A nuclear localization signal
(NLS), which lies in 31-RRRGL-35 of the protein, is responsible for the nucleolus
targeting of human ANG [26]. However, the ANG NLS does not confer nuclear
import through the pathway used by conventional NLSs in that importins and Ran
are not required [27]. The process is also independent of microtubules and
lysosomes [28]. Since the molecular weight of ANG is less than the limit of
nuclear pore size (50-kDa), the most probable mechanism for ANG
nuclear/nucleolus import may involve passive diffusion of ANG through the
nuclear pore and NLS-mediated nuclear/nucleolus retention [27].
Roles of ANG in Diseases
ANG induces tumor growth
It was reported that the expression of ANG was upregulated in
various types of human cancers, including breast, cervical, colon, colorectal,
endometrial, gastric, liver, kidney, ovarian, pancreatic, prostate, and
urothelial cancers, as well as astrocytoma, leukemia (acute myeloid leukemia
and myelodysplastic syndrome), lymphoma (non-Hodgkin’s), melanoma,
osteosarcoma, and Wilms’ tumor [29]. This indicates a close relationship
between ANG and tumor development.
Angiogenin was once thought to promote cancer progression by its
angiogenic activity, and target HUVE and HuASM cells as described above.
Recently ANG was reported to constantly translocate to the nucleus of HeLa
cells in a cell density-independent manner. Downregulation of ANG expression in
HeLa cells resulted in a decrease in rRNA transcription, ribosome biogenesis,
proliferation, and tumorigenesis [30]. These results point to a direct effect
of ANG on cancer cells for the first time with a similar action manner as in
HUVE cells. Latter studies on prostate cancer cells showed that ANG could
directly stimulate PC-3 proliferation, and underwent nuclear translocation in
PC-3 cells grown both in vitro and in mice. Blockade of nuclear
translocation of ANG by neomycin inhibited PC-3 cell tumor growth in athymic
mice and was accompanied by a decrease in both cancer cell proliferation and
angiogenesis [29]. In addition, ANG could be an effective substrate for HT-29
cells adhesion during metastasis [31]. Thus, it is clear that ANG takes part in
cancer development by stimulating both angiogenesis and cancer cell
proliferation. However, whether the mechanisms of ANG that act on HUVE cells
and cancer cells are similar is unknown yet.
ANG may be related with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive late-onset
neurodegenerative disorder affecting upper and lower motoneurons (MNs). VEGF
was the first angiogenic factor shown to contribute to the pathogenesis of ALS
[32]. ANG was recently identified as the second angiogenic factor related to
this disease. First, allelic association studies of Irish and Scottish ALS
populations identified chromosome 14q11.2 where the ANG gene is located as a
candidate region. Later a synonymous single nucleotide polymorphism (rs 11701)
was found to be associated with Irish and Scottish ALS populations by
sequencing 1629 ALS patients [33]. Thereafter, seven missense mutations in the
ANG gene were identified in 15 patients with either familial or sporadic ALS by
sequencing the same 1629 ALS patients [34]. To date, mutations of the ANG gene
have been detected in the Irish, Scottish, Italian, and North American patients
with ALS diseases [34-39].
Angiogenin may exert neuroprotective activities on motoneurons in
the central nervous system. First, as an angiogenic factor, ANG protects MNs by
increasing neurovascular perfusion. Studies on the functional consequence of
those detected ANG mutations showed that the mutants diminished ANG’s
ribonucleolytic activity, nuclear translocation, or both. A correlative
reduction in the HUVE cell proliferative and angiogenic activities was observed
[35,36], which may contribute to the induction of ALS.
Second, ANG may protect MNs via its direct effects on the neurons themselves.
Mouse ANG-1 (mAng-1) was found to be strongly expressed in motor neurons in the
spinal cord and dorsal root ganglia as well as in post-mitotic MNs derived from
P19 cells. Its expression was found in the growth cones and neurites.
Inhibition of the ribonucleolytic activity of human ANG affected path finding
by P19-derived neurons [40]. Cultured P19 EC cells could internalize both
wild-type ANG and the variants implicated in ALS. However, wild-type ANG could
induce P19 EC cell differentiation and the extending of the neuritis, whereas
the variants lost these capacities. Wild-type ANG was able to protect neurons
from hypoxia-induced cell death, but the variants lacked the neuroprotective
activity [41]. These findings provide a causal link between mutations in ANG
and ALS.
ANG acts in other diseases
Angiogenin may also play roles in a variety of non-malignant angiogenesis-dependent
diseases such as endometriosis [42], peripheral vascular disease
[43], inflammatory bowel disease (IBD) [44], rheumatoid arthritis
[45], diabetes [46], and so on. In these disorders, ANG expression
levels increase and ANG may contribute to the local pathological angiogenesis
conditions.
Perspectives
Identifying the physiological RNase substrate of ANG
The ribonucleolytic activity of ANG is essential for its functions.
Although ANG was reported to be able to catalyze degradation of 18S and 28S
rRNA [47], tRNA from Xenopus oocytes [48], and 5S RNA from Saccharomyces
cerevisiae and Escherichia coli [49], the physiological substrate of
ANG is still unknown. It is unlikely that ANG has a specific recognition
sequence for catalysis. Instead, the target may have a specific secondary
structure, such as a hairpin or a pseudo-knot, or may be part of a protein-nucleic
acid complex. The poor catalytic activity of ANG may have evolved to maximize
specificity for the target substrate [50]. The natural substrate of ANG may
reside in the nucleolus of its target cells where it accumulates. Since rRNA
transcription is always coupled and coordinated with its processing, rRNA could
be a candidate substrate of ANG. The identification of its physiological
substrate should be a great help for the complete description of ANG’s
activities.
Developing ANG nuclear translocation inhibitors
The function of ANG in mediating both endothelial cell and cancer
cell proliferation is related to rRNA transcription and depends on nuclear
translocation [21,30]. Thus, the process of ANG nuclear translocation seems to
be an ideal target for anti-ANG drug discovery. Neomycin seems to be such a
promising drug because it blocks nuclear translocation of ANG in PC-3 cells and
inhibits tumor establishment and growth in athymic mice by inhibiting tumor
angiogenesis and prostate cancer cell proliferation, respectively. In other
words, this drug has a combined benefit of chemotherapy and antiangiogenesis
therapy. Now the Hu group is evaluating the therapeutic value of neomycin and
its nontoxic derivative neamine against cancers [29]. We reason that elucidating
the mechanisms of ANG nuclear translocation would provide new targets for
developing such kinds of inhibitors.
Identifying ANG-interacting proteins
Since protein interactions are critical in every biological process,
interactions between ANG and other proteins should mediate or modulate a series
of biological activities in ANG-induced angiogenesis and tumor cell growth.
Unfortunately, few proteins have so far been identified as binding partners of
ANG. To identify more mediators or modulators of ANG activity, yeast two-hybrid
technology was used in our laboratory and 21 proteins were identified as
potential ANG-interacting molecules from the human liver cDNA library and heart
cDNA library, including cytoskeleton proteins such as alpha-actinin 2 (ACTN-2)
[51], regulatory proteins such as follistatin (FS) [52], and extracellular
matrix proteins such as fibulin-1 [53]. Through interacting with ACTN-2, ANG
may regulate the movement or the cytokinesis of the cells. Follistatin may act
as a regulator on angiogenin’s actions. Interaction between ANG and fibulins
may facilitate cell adhesion. The concrete significance of those interactions
is under study now.
In summary, angiogenin
plays important roles in many pathological states, and could be an ideal target
for disease treatment. Although many molecules have been reported to exert
antitumor effects, such as anti-ANG monoclonal antibodies [54], ANG-binding
peptides [55], ANG antisense RNA [56], and its ribonuclease inhibitors [10],
they all antagonize angiogenin itself, and may have significant side effects.
An ideal angiogenin-oriented drug could only be made possible after fully
elucidating the mechanism of action of angiogenin and identify a
disease-specific process.
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