ARTICLE
Auteur(s) : Evangelia
Papadimitriou, Constantinos Mikelis, Evgenia Lampropoulou,
Marina Koutsioumpa, Katerina Theochari, Sotiria Tsirmoula,
Christina Theodoropoulou, Margarita Lamprou, Evanthia Sfaelou,
Dionyssios Vourtsis, Panagiotis Boudouris
Laboratory of Molecular Pharmacology, Department
of Pharmacy, University of Patras, Patras, Greece
accepté le 12 Juin 2009
Pleiotrophin (PTN) is a secreted heparin-binding growth factor
that takes part in many different processes, such as cell growth
and survival, cell migration, angiogenesis and neurite outgrowth.
It is also known as heparin-binding growth-associated molecule [1,
2], heparin affin regulatory peptide [3], heparin-binding growth
factor-8 [4], protein 18 kDa [5], heparin-binding neurotrophic
factor [6, 7] and osteoblast-specific factor [8]. PTN is highly
homologous to midkine (MK), with which it shares 45-50% sequence
identity, forming a family of growth factors [6, 9]. It is highly
conserved across different species: more than 90% identity has been
observed among the sequences of chicken, rat, mouse, bovine and
human [10], while homologues have been also reported in fish, frogs
and insects [11].
Human PTN protein and gene/promoter structure
PTN consists of 168 amino acids, the mature peptide having
136 amino acids as a result of cleavage of the signal peptide
[12, 13]. The calculated mass of the mature protein was determined
by plasma desorption time-of-flight mass spectrometry as
15,291 kDa, but in SDS-PAGE it appears as 18 kDa [2], due
to the fact that the molecule is rich in cationic amino acids,
mainly lysines, that form random coils at both N- and C-terminal
ends [12, 14]. The peptide also contains 10 conserved
cysteines that participate in the formation of five disulfide bonds
[2, 15, 16], and three potential nuclear targeting sequences
K-R/K-X-R /K [2]. PTN does not contain any potential sites for
N-glycosylation or other post-translational modifications [1, 2]
and its binding to heparin is mediated by the two central regions
that are homologous to the thrombospondin type I repeat (TSR-1)
[14]. More recent data suggest that the carboxyl terminal
TSR-1 domain is the main heparin-binding site of PTN [17].
The human ptn gene has been identified as being on chromosome
7 band q33a, having a minimum size of 42 kDa, and
containing at least seven exons. The open reading frame is located
on four exons and the boundaries between introns and extrons seem
to be conserved among species in the PTN/MK family [18]. The signal
peptide and the first five amino acids of the mature protein are
located in exon 2, while the core region is split into exons
2 and 3, containing six and four cysteine residues
respectively. Exon 4 comprises the C-terminus of PTN that
contains a putative nuclear translocation signal based on its
homology with histone Hl [19]. The 5’ untranslated region is unique
in the human ptn gene compared with other species [20], while there
may be multiple 5’ untranslated regions derived from alternative
splicing [21] that may contribute to cell or tissue-specific
regulation of PTN expression [19]. From what is known to date, the
promoter of the human ptn gene contains sequences for the binding
of several transcription factors, as shown in figure 1.
Regulation of PTN expression
Although PTN seems to have significant biological functions, little
is still known on the regulation of its expression. It is known
that ptn gene expression is regulated in a cell type- and
time-dependent manner [5, 13, 19]. It is also known that it is
up-regulated during specific diseases, such as rheumatoid arthritis
[24], osteoarthritis [25], after injury [26, 27] or in cancer (see
below). Up-regulation of PTN expression has been mentioned for
tumor necrosis factor α and epidermal growth factor [24], ciliary
neurotrophic factor [28], members of the fibroblast growth factor
(FGF) family, such as FGF2 and FGF10 [29, 30],
platelet-derived growth factor [31, 32], cAMP [33] hypoxia [32],
serum [34], hydrogen peroxide [35] and endothelial nitric oxide
synthase [36]. Contradictory results have been published on
retinoic acid, which induces PTN expression in some cells [9, 37]
or tissues [30], but has no effect on other types of cells [31].
Concerning transcription factors, ptn gene expression is directly
affected by HOXA5 [38] and AP-1 [35], after direct binding to the
corresponding response elements on the ptn promoter. Finally, loss
of the tumor suppressor gene PTEN leads to up-regulation of PTN
expression, mediated by the PTEN-PI3K-AKT pathway [39].
Biological activities of PTN
The initial reference involving PTN suggested that it plays a role
in the maturation and growth of brain [5]. Since then, the
importance of PTN in the nervous system has been well described
[13, 27, 28, 33, 40-51]. PTN is over-expressed in neurodegenerative
diseases [52] and exhibits a protective or/and trophic effect on
dopaminergic neurons in vitro and in vivo [45, 46, 48, 53].
Regarding the muscular system, PTN is expressed in developing
muscle in vivo [1, 13, 54], is up-regulated during in vitro
myogenesis and soleus muscle regeneration, and can be found in
newly formed myotubes and perfused activated myoblasts [55].
Moreover, PTN mRNA is present in smooth muscle [56] and cardiac
muscle cells [57, 58], is down-regulated during postnatal
differentiation of the myocardium [58], up-regulated in heart
failure [59], and potentiates cardiomyocyte cell death by apoptosis
[60].
PTN is expressed in the fetus liver but its expression gradually
decreases [61], although it seems to be involved in liver
regeneration [32, 61]. PTN is expressed in the developing kidney
mesenchyme [57] and induces formation of branching tubules in an
immortalized ureteric bud cell line cultured three-dimensionally in
an extracellular matrix gel [62]. PTN is detected during lung
development and in embryonic bronchial epithelial cells [57], and
regulates lung epithelial cell proliferation and differentiation
during fetal lung development [63]. It is also normally expressed
in the epithelial ridge of cochlea, suggesting a role in auditory
function [64].
In females, PTN is expressed in the uterus, and its expression
is dependent on the estrous cycle [56, 65], which it seems to
affect [65]. In human mammary gland, PTN is detected in alveolar
myoepithelial, epithelial, endothelial and vascular smooth muscle
cells [66], and its expression is increased in both terminal end
bud and mature ducts in the process of mammary branching
morphogenesis [67]. PTN is involved in ectopic endometriosis [68],
and female mice deficient in both PTN and MK have shown
abnormalities of reproduction [65]. In males, PTN plays a role in
normal spermatogenesis. It is expressed in Leydig cells of the
testis and is up-regulated in both human Peyronie’s and Dupuytren’s
disease [69, 70]. Dominant negative PTN mutant male mice show
sterility, atrophic testes and strikingly apoptotic spermatocytes
[71].
PTN promotes proliferation, differentiation and proper
attachment of osteoblasts [72, 73], and induces chemotaxis,
proliferation and differentiation of human osteoprogenitor cells,
as well as both bone and cartilage formation in athymic mice [74].
It is also involved in angiogenesis in the growth plate of mice
[75], and regulates the ectopic bone-inducing activity of rhBMP-2
[76]. Furthermore, PTN is a vital signaling molecule in regulating
periosteal bone formation and resorption in response to four-point
bending of right tibias in C57BL/6J mice [77]. Interestingly, mice
that over-express PTN tend to have increased bone growth [78], and
although PTN-deficient mice seem to have normal bone formation
[79], they show growth retardation in the weight-bearing bones by
two months of age, and osteopenia during adulthood [80]. PTN is
found in developing [81] and adult [82] nasal cartilage, and
participates in the proteoglycan synthesis in the developing matrix
of fetal cartilage [83]. It is an autocrine growth factor in
cartilage [25], is increasingly expressed in the early stages of
osteoarthritis [25, 84] and an increase at its mRNA levels is
provoked by sclerotic, subchondrial osteoblasts in osteoarthritic
cartilage [85]. Whether PTN improves or deteriorates osteoarthritis
is not known to date.
Biological activities related to cancers
Cancer cells in vitro
A role for PTN in human cancers was suggested after its detection
in conditioned media of the highly malignant breast cancer cell
line MDA-MB231 [86]. Since then, screening of various human cell
lines and tumor specimens revealed that PTN is expressed as an
autocrine or/and paracrine growth factor by various cancer cells,
including human breast [87-89], prostate [29, 87, 90, 91], ovarian
[87] and lung [92] cancer, choriocarcinoma [93], melanoma [87, 94],
glioblastoma [95-98] and pancreatic carcinoma cells [99]. Multiple
myeloma (MM) cell lines and malignant cells from MM patients’ bone
marrow produced and secreted PTN into the cell culture supernatants
and ptn gene expression correlated with the patients’ disease
status. Inhibition of PTN with a polyclonal anti-PTN antibody
reduced growth and enhanced apoptosis of MM cell lines and freshly
isolated bone marrow tumor cells from MM patients in vitro [100].
PTN mRNA is also selectively detected in the meningothelial cells
of meningiomas [101], and PTN expression is up-regulated after loss
of the tumor suppressor gene PTEN [39]. Interestingly, it has
recently been suggested that decrease of PTN expression in U87MG
cells induces tetraploidy and aneuploidy, and arrests cells in the
G1 phase of the cell cycle, suggesting that PTN signaling may
have a critical role in chromosomal segregation and cell cycle
progression [102]. Moreover, PTN disrupts cytoskeletal protein
complexes, ablates calcium-dependent homophilic cell-cell adhesion,
stimulates ubiquitination and degradation of N-cadherin,
reorganizes the actin cytoskeleton and induces a morphological
epithelial-mesenchymal transition in PTN-stimulated U373 cells
[103]. PTN is also involved in hepatocarcinogenesis and has an
anti-apoptotic activity against TGFβ1 in hepatoma cell lines
[104]. Finally, in line with the notion that PTN may significantly
stimulate tumor progression, independently of its effect on the
cancer cells themselves, PTN secretion from MCF-7 breast
cancer cells stimulates epithelial island formation, activation of
stromal fibroblasts, extensive remodeling of the microenvironment
and activation of markers of aggressive breast cancer in
co-cultures of PTN-expressing MCF-7 and NIH 3T3 cells
[105]. It also affects tumor angiogenesis, as discussed more
extensively below.
Conversely, there are cases where PTN has been shown to
negatively regulate tumor cell growth. For example, PTN mRNA levels
are decreased in colorectal cancers compared with those in normal
adjacent mucosa [106]. It has been detected in lysates and
conditioned medium from contact-arrested NIH 3T3 fibroblasts,
but not in cells transformed by the ras oncogene [107], and its
expression is up-regulated in confluent compared with actively
proliferating cells [108, 109]. Its expression is low or absent in
neuroblastomas with a poor prognosis [110], and negatively affects
growth and migration of several glioma cells lines [111, 112].
Tumor angiogenesis in vitro
Besides a significant role in the biology of tumor cells
themselves, PTN seems also to affect the angiogenic potential of
tumor cells. Firstly, PTN stimulates angiogenic functions of
endothelial cells in vitro [113-117] and induces embryoid body
angiogenesis [118] and transdifferentiation of monocytes into
functional endothelial cells [119-121]. In the same line, it
increases the in vitro angiogenic potential of several tumor cells,
such as multiple myeloma [120], breast [122] and prostate [91]
cancer cells.
In contrast to a positive regulation of in vitro angiogenesis by
PTN, there are also data that support a negative regulation. First
of all, PTN directly binds and inhibits the effect of vascular
endothelial growth factor (VEGF) on endothelial cell proliferation,
migration and tube formation [123, 124]. It also decreases the
expression of the VEGF receptor KDR, another mechanism through
which it potentially inhibits VEGF angiogenic activities in vitro
[125]. Finally, decrease in the expression of endogenous PTN in
C6 glioma cells significantly increased the angiogenic
potential of these cells in vitro, partially due to increased
availability and activity of VEGF [111].
Tumor growth and angiogenesis in vivo
Much in vivo data suggest that PTN plays a role in angiogenesis of
tumors that grow in nude mice. This was initially shown in
NIH-3T3 cells that constitutively over-expressed PTN. When
these cells were implanted into the flanks of nude mice, they
tended to form tumors with significant neovascularization compared
with the mock-transfected cells [126]. In the same line,
over-expression of PTN in a human adrenal carcinoma cell line
SW13 promotes not only in vivo tumor growth, but also
tumor-induced angiogenesis, suggesting that constitutive PTN
signaling fully regulates the angiogenic switch [127]. Expression
of PTN in breast cancer MCF-7 cells stimulates tumor growth,
remodeling of the microenvironment and tumor-induced angiogenesis
in vivo [105, 122].
Ribozyme-mediated depletion of HERV-PTN mRNA in human
choriocarcinoma suggests that PTN is an essential and rate-limiting
factor for choriocarcinoma growth, invasion, and angiogenesis in
vivo [93]. Moreover, RNA interference-mediated gene silencing of
PTN suppresses glioblastoma growth and angiogenesis in vivo [128].
Finally, PTN antisense expression in human prostate cancer LNCaP
cells inhibits LNCaP cell-induced angiogenesis in vivo in the
chicken embryo chorioallantoic membrane [91].
On the other hand, there is also evidence that PTN can act as an
angiostatic factor. For example, vascularization was significantly
decreased in neuroblastoma xenografts that over-express PTN and
that are resistant to the DNA-topoisomerase I inhibitor irinotecan
[110]. Similarly, PTN antisense expression in rat glioma
C6 cells, increased C6 glioma cell-induced angiogenesis
in vivo in the chicken embryo chorioallantoic membrane [111]. In
both cases, direct binding of PTN to VEGF has been discussed as the
possible reason, although other mechanisms may be also
involved.
Structure-function data
Many studies have been undertaken in order to determine which
regions of PTN are responsible for its diverse functions, in an
effort to identify the molecular mechanisms involved and to
identify possible therapeutic targets or/and agents. Kilpelainen
et al. suggested that the two TSR-1 motifs are
responsible for the interaction of PTN with heparin, an interaction
associated with many of the biological activities of PTN [14]. More
recent data suggest the involvement of only the carboxyl terminal
TSR-1 motif in heparin binding [17, 129], and the mitogenic,
transforming and angiogenic activities of PTN in vitro and in vivo
in nude mice [129].
It has been shown that PTN exists in two naturally occurring
forms, PTN15 and PTN18, with differential interactions with
its receptors anaplastic lymphoma kinase (ALK) and receptor protein
tyrosine phosphatase β/ζ (RPTPβ/ζ), and different activities.
PTN18 interacts with RPTPβ/ζ and induces glioma cell
migration, while PTN15 interacts with ALK and induces glioma
cell proliferation [97]. The two forms of PTN differ in their
carboxyl terminus, which is being investigated for its role in
tumor growth and angiogenesis. It has long been shown that the
C-terminal lysine-rich domain of PTN (amino acids 111-136) is not
involved in neurite outgrowth activity, but it seems to play a key
role in the mitogenic and tumor formation activities of PTN [130].
A truncated PTN lacking the C-terminal 111-136 portion
inhibits tumor development by inhibition of both endothelial and
breast cancer cells [131]. The exact mechanism of action of the
C-terminal lysine-rich domain of PTN is not known. It has been
suggested that it acts through binding to ALK [132], or RPTPβ/ζ
[133] and antagonizes PTN binding and activity [132, 133]. Since
this domain of PTN seems to play an important role in its
biological activities related to tumor growth and angiogenesis,
more work is needed to identify the molecule(s) with which it
interacts, the result(s) of such interactions, as well as its
possible therapeutic potential.
Receptors, molecular mechanisms and interactions
with other molecules involved in PTN actions related
to angiogenesis and cancer
Syndecans
The first identified receptor for PTN has been N-syndecan [134].
The interaction of PTN with N-syndecan takes place via its heparan
sulfate side chains [134, 135] and is mediated by both
TSR-1 domains of PTN [136, 137]. Binding of PTN to N-syndecan
promotes several PTN-induced actions in the nervous system [135,
138-140].
Besides the nervous system, possible involvement of N-syndecan
in PTN activities has been mentioned in osteoblasts [73, 78], and
in parenchymal cells in adult and embryonic liver [61]. No
involvement of N-syndecan in PTN-induced activities related to
angiogenesis and cancer has been mentioned, nor is it known whether
other syndecans interact and mediate PTN-induced actions.
Anaplastic lymphoma kinase (ALK)
ALK is a 220-kDa receptor tyrosine kinase (RTK) encoded by the alk
gene on chromosome 2p23. ALK was first identified as part of the
NPM-ALK oncogenic fusion protein, resulting from the (2;5)(p23;q35)
translocation that is frequently associated with anaplastic
large-cell lymphoma [141]. Full-length ALK has the typical
structure of an RTK, with a large extracellular domain, a
lipophilic transmembrane segment, a cytoplasmic tyrosine kinase
domain, and belongs to the insulin receptor superfamily. It was
initially described as an orphan RTK that shows restricted tissue
distribution and is regulated during organ development [142, 143].
PTN was initially identified as a potential ligand of ALK, based on
a genetic screen by peptide ‘phage display [144]. Different groups
have since suggested ALK to be a functional PTN receptor [144-147].
In support of this, the expression pattern of PTN partially
overlaps with that of ALK in the rodent developing nervous system
[144].
Beyond ALK expression in the nervous system, cultured
fibroblasts and endothelial cells, it has also been detected in
osteoblastic cells [148] and chondrocytes [25], in pancreatic and
breast carcinoma [144, 149], melanoma [150], neuroblastoma [151]
glioblastoma [145, 146] and non-Hodgkin’s lymphoma [152].
On the other hand, ALK expression is low in a wide variety of
soft tumors [153], and is characterized by limited tissue
distribution [142]. Moreover, recent studies performed by different
groups argue against PTN as a specific ALK ligand, since binding or
activation of ALK by PTN cannot be detected [150, 154-158].
A possible explanation to the confusion in the literature may
be the differential activation of ALK by the two naturally
occurring forms of PTN [97], or the indirect PTN-induced ALK
activation through PTN-dependent inactivation of the RPTPβ/ζ
[159].
Receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ)
RPTPβ/ζ was initially isolated from neural tissue as a
transmembrane protein-tyrosine-phosphatase (PTPase) that consists
of a putative signal peptide, a very large extracellular domain
containing an N-terminal sequence homologous to carbonic anhydrase,
a transmembrane region and a cytoplasmic portion that contains two
repeated PTPase-like domains [160]. A shorter transmembrane
and two secreted isoforms corresponding to the extracellular
portions of the long and short transmembrane isoforms have been
described, all considered splice variants of RPTPβ/ζ [161-163]. The
short transmembrane isoform lacks 859 amino acids from the
extracellular domain [161] and also interacts with PTN. Phosphacan,
the secreted isoform that corresponds to the extracellular portion
of the long RPTPβ/ζ, is also able to bind PTN [162], and is
considered to modulate cell interactions and developmental
processes in the nervous system [164]. Changes in chondroitin
sulfate on phosphacan are developmentally regulated and regulate
phosphacan’s affinity for PTN [165]. Phosphacan short isoform that
corresponds to the extracellular portion of the short RPTPβ/ζ, is
not a proteoglycan [163] and has not been shown to interact with
PTN. Apart from the RPTPβ/ζ splicing variants that are normally
expressed, under physiological conditions, RPTPβ/ζ is cleaved by
matrix metalloproteinase 9, tumor necrosis factor-α converting
enzyme, presenilin/γ-secretase [166] and plasmin [167], leading to
secreted, transmembrane, or cytoplasmic forms of, not yet, fully
identified biological significance.
It has been suggested that PTN binding to RPTPβ/ζ leads to
dimerization of the receptor and inhibition of the PTPase activity.
The PTN-dependent RPTPβ/ζ inactivation was shown to lead to
increased phosphorylation of β-catenin [168], β-adducin [169] and
Fyn [170], thus regulating cytoskeletal stability, cell plasticity
and cell-cell adhesion mechanisms [169]. In U373 cells, PTN
induced increased tyrosine phosphorylation of different RPTPβ/ζ
substrates required for epithelial-mesenchymal transition [103]. On
the other hand, PTN binding to RPTPβ/ζ in endothelial cells leads
to dephosphorylation and thus activation of c-src, focal adhesion
kinase, phosphatidylinositol-3-kinase and mitogen-activated protein
kinases, all participating in PTN-induced endothelial cell
migration and tube formation on matrigel [116]. We have more
recently shown that in order for RPTPβ/ζ to induce cell migration,
the presence of ανβ3 integrin is required.
RPTPβ/ζ and ανβ3 form a functional complex on
the surface of endothelial and glioma cell lines, and RPTPβ/ζ seems
to be responsible for β3 tyrosine phosphorylation
through the activation of c-src [112]. PTN inhibits migration of
cells that do not express ανβ3, even if these
cells express RPTPβ/ζ [112], however, the exact mechanism(s)
involved are not known.
Other possible (co-)receptors
It has long been shown that PTN interacts with several
proteoglycans (PGs) with different affinities [171], interactions
that seem to contribute to PTN dimerization [172] or storage into
the extracellular matrix [113]. Among PGs, many reports have
implicated a role for chondroitin sulfate (CS) PGs in the
PTN-mediated signaling pathway. It has been shown by several
studies that PTN interacts especially with over-sulfated CSs [162,
165, 173-175], an interaction important for the development of the
nervous system [173, 176, 177] and for growth and/or progression of
tumors [178]. Versican, a CS-PG with a high content of the E
disaccharide units, was found to bind strongly PTN, an interaction
abolished by chondroitinase ABC digestion [179]. Similarly, the
appican CS chain from rat C6 glioma cells, but not that from
SH-SY5Y neuroblastoma cells that contained no E disaccharide, was
found to bind specifically PTN [180]. These findings indicate that
the E motif is essential for the interaction of the CS chains with
PTN. Analysis of the oligosaccharides isolated from embryonic
CS/dermatan sulfate (DS) chains revealed that octasaccharide is the
minimal size capable of interacting with PTN at a physiological
salt concentration, and that PTN binds to multiple sequences in
embryonic CS/DS chains with distinct affinity [181].
PTN also binds ανβ3, but not
α5β1 integrin, an interaction that is
responsible for PTN-induced cell migration in both endothelial and
glioma cell lines [112]. Integrin ανβ3 forms
a functional complex with RPTPβ/ζ on the cell surface, both
components of which are required for the stimulatory effect of PTN
on cell migration. Activation of β3 through
phosphorylation of its cytoplasmic tyrosine 773, is required, but
is not sufficient to transduce the stimulatory effect of PTN [112].
Further studies are being conducted to elucidate the signaling
pathway involved. Interestingly, ανβ3 is not
a receptor for MK [112], in contrast to all other PTN receptors
discussed to date.
Finally, PTN binds nucleolin [182], a 100 kDa
multifunctional protein present in the nucleus, cytoplasm, and on
the surface of some types of cells, including endothelial [183] and
cancer [184, 185] cells. HB-19 pseudopeptide, a specific
antagonist that binds the C-terminal tail of nucleolin, has been
shown to suppress the growth of tumor cells and angiogenesis in
various in vitro and in vivo experimental models [184]. Nucleolin
is considered to be a low affinity receptor for PTN, and has been
suggested to possibly import PTN into the nucleus [182]. PTN binds
nucleolin through its C-TSR-1 domain with a Kd value of
1.3-1.4 x 10-6 M [186] in the absence of heparin. This
binding is strongly inhibited by heparin even though it has not
been clarified whether the inhibition was caused by the binding of
heparin to PTN or nucleolin [182]. Following its binding to cell
surface nucleolin, PTN is internalized in a temperature-sensitive
manner, which is independent of heparin and CS PGs [186]. What is
the role of the interaction of PTN with nucleolin and of the
subsequent PTN internalization remains unknown, but is under
further investigation for its possible implication in the effects
of PTN on tumor growth and angiogenesis.
Conclusion
Although many aspects remain obscure, PTN seems to be significant
for tumor growth and angiogenesis, possibly through diverse
mechanisms. Clarification of the receptors, as well as the
signaling pathways involved, is of great importance, both for
increasing our knowledge concerning cancer growth, and for
developing new therapeutic strategies.
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