Pleiotrophin (PTN) is a secreted cell-signaling cytokine that acts as a growth factor associated with the extracellular matrix (ECM). It was discovered practically simultaneously by several laboratories nearly 25 years ago; thus, it initially received several names, as follows: HBGF-8 (heparin-binding growth factor (Milner et al. 1989); HB-GAM (heparin-binding growth-associated molecule) (Rauvala 1989; Merenmies and Rauvala 1990); HBNF (heparin-binding neurotrophic factor) (Kovesdi et al. 1990); OSF-1 (osteoblast-specific factor 1) (Tezuka et al. 1990), and HARP (heparin affinity regulatory peptide (Courty et al. 1991)). Some of these names are still in use in the literature, depending on the area of knowledge that the information generates; therefore, this can sometimes complicate the clear identification of the pleiad of actions and effects reported for PTN.
PTN shares high homology (>50%) with another peptide, denominated midkine (MK); both are highly conserved throughout evolution and are found in several species, ranging from Drosophila to humans (Kadomatsu and Muramatsu 2004). This conservation means that although both peptides could have many functions in common and could participate in similar functions, they also possess more particular, specific, and nonredundant functions. This is evident when both are simultaneously knocked out in mice: they display severe abnormality phenotypes. However, when independently knocked out, PTN−/− and MK−/− mice are far from being completely normal and exhibit moderate, but different, abnormalities (Muramatsu et al. 2006; Zou et al. 2006; Gramage and Herradon 2010; Himburg et al. 2012; Vicente-Rodriguez et al. 2013; Gonzalez-Castillo et al. 2016), which denotes that although both peptides could present overlapping or similar functions, they are also clearly involved in different roles.
Proteolytic cleavage of PTN has been described by plasmin (Polykratis et al. 2005) and MMP-2 (Dean et al. 2007) (Fig. 3) and has been related with different biological activities: tumor growth and angiogenesis, respectively. Cleavage by MMP-2 separates the two thrombospondin-1 repeats, yielding two fragments of approximately 6.6 and 6.4 KDa (Dean et al. 2007). Consequently, cleavage abrogates the mitogenic activity of PTN and significantly reduces its induced cell migration. Also, PTN binding with vascular endothelial growth factor (VEGF) prevents its cleavage by MMP-2 (Dean et al. 2007). Therefore, MMP-2 modulates PTN-induced cell proliferation and migration, and this action changes in the presence of VEGF.
On the other hand, cleavage by plasmin could theoretically generate up to five different small peptides of 16, 13, 10, 7, and 5.5 KDa (Polykratis et al. 2005). At least two of these, 16 and 13 KDa, have been detected by others (Bohlen and Kovesdi 1991; Hampton et al. 1992). Cleavage in the second site of the soluble form of PTN (K92–K93) yields two peptides, each containing only one β-sheet domain, which positively regulates angiogenesis in vitro, whereas PTN containing both β-sheet domains exert an inhibitory effect (Polykratis et al. 2005). Additionally, the presence of both domains is required when binding to VEGF165 (Heroult et al. 2004). Additionally, the third point-of-cleavage site removes a still unknown small portion of the C-terminal region, which is also implicated in its angiogenic activity (Bernard-Pierrot et al. 2001; Papadimitriou et al. 2001, 2009). This cleavage is necessary for the binding of PTN to anaplastic lymphoma kinase (ALK) receptor (Bernard-Pierrot et al. 2002; Ryan et al. 2016). This third cleavage site (question mark in Fig. 3) could correspond to the truncated form described by Lu et al. (2005), which is naturally processed by proteolytic cleavage and that has 12 residues less in the C-terminus, yielding a protein of an apparent MW of 15 KDa, named PTN15, to distinguish it from the complete PTN18 (Lu et al. 2005). Therefore, PTN is subject to regulatory proteolytic cleavage, at least by plasmin and MMP-2 and perhaps possibly by other proteases, which controls and organize their effects once secreted into the ECM.
Expression Profile of PTN
Since the first descriptions of the PTN expression profile (Nakamoto et al. 1992; Vanderwinden et al. 1992), increasing evidence has accumulated on the pleiotropic expression of the PTN peptide. During mammalian embryogenesis, PTN is highly expressed in the central nervous system (CNS) and the peripheral nervous system (PNS), as well as in organs undergoing branching morphogenesis, including the salivary glands, lung, and kidney, the digestive and skeletal systems, sense organs and facial processes, and limbs (Mitsiadis et al. 1995). PTN is mainly located in the basement membrane of the developing epithelium and in mesenchymal tissues undergoing remodeling, suggesting that it may play an important role in mesenchymal–epithelial interactions (Weng and Liu 2010). In the adult stage, PTN expression is mainly restricted to the CNS and to only few cell types therein (Reviewed in (Gonzalez-Castillo et al. 2014)). However, under pathological conditions, it can be overexpressed by quiescent hepatic stellate cells (HSC) during experimental fibrogenesis, comprising as a strong mitogenic signal for hepatocytes to limit damage to parenchymal cells in biliary-type liver fibrogenesis (Antoine et al. 2005). In addition, its expression in pathologic human intervertebral discs is associated with neovascularization of diseased or damaged disc tissue (Johnson et al. 2007), and it also is highly expressed in some types of cancers (see later).
The existence of at least two naturally occurring isoforms of PTN (Lu et al. 2005) and the recently demonstrated fact that each of these binds differentially to different receptor complexes (Ryan et al. 2016), as well as the multiple peptide that can be generated by proteolytic cleavage, mainly from plasmin and MMP-2 (previously described), imply the need for reinterpretation, or at least reconsideration, of practically all of the results reported to date for PTN functions and its effects, in order to correctly adjudicate each effect on each peptide fragment (for instance, PTN18, PTN15, or even others that are smaller), and/or on the respective receptor activated and signaling pathway triggered (see later). Additionally, the location and regulation of the expression of the enzymes that cleave PTN peptide acquire relevance in terms of regulating its actions.
PTN Signaling Through a Variety of Receptors or a Multireceptor Complex
As a growth factor, PTN signals are generally related with cell growth, proliferation, and differentiation, but PTN has also has been involved in other functions by acting through different receptors.
Mainly, PTN can bind and signal via receptor protein tyrosine phosphatase ζ (RPTPζ), EC = 184.108.40.206 (Maeda et al. 1996, 1999; Meng et al. 2000), which is a transmembrane chondroitin sulfate proteoglycan present in two isoforms (shorter and full length), which in turn also binds with various cell adhesion molecules (NrCAM, L1/Ng-CAM, contactin, N-CAM, and TAG1), growth factors (PTN, MK, and fibroblast growth factor 2 (FGF-2)), and ECM molecules (amphoterin, tenascin-C, and tenascin-R) (Reviewed in (Maeda et al. 2010)). The effects exerted through this receptor can be mainly attributed to PTN18, rather than to PTN15 (Ryan et al. 2016).
The intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa (RPTP-κ) are proteolytically processed into isoforms that possess opposing effects on β-catenin activity. The RPTP-κ transmembrane P subunit interacts with and sequesters β-catenin at the cell membrane, where it can associate with E-cadherin and promote intercellular interactions. At high cell density, further processing of the P subunit yields a phosphatase intracellular portion (PIC) subunit, which chaperones β-catenin into the nucleus, where it can function to activate transcription (Sanchez-Morgan et al. 2011). PTPζ/β also dephosphorylates β-catenin, although PTPζ/β is inactivated when stimulated with PTN (Meng et al. 2000). This stimulation induces a morphological epithelial-to-mesenchymal transition in human GBM cells (Perez-Pinera et al. 2008). Thus, cleavage of the constitutively active RPTPζ/β would yield the same effect as PTN stimulation (Pariser et al. 2005). Therefore, PTN signaling can interact with Wnt signaling by altering β-catenin activity (Weng and Liu 2010).
According to Ryan et al. (2016), PTN15 is the truncated form that can act via anaplastic lymphoma kinase (ALK) receptor and exert reported actions (Stoica et al. 2001; Powers et al. 2002). Consequently, evidences suggesting that the action of PTN on ALK could occur through its previous interaction with RPTPζ (Perez-Pinera et al. 2007) must be reconsidered or at least reinterpreted.
Additionally, PTN can act through several other receptors as follows (Reviewed in (Gonzalez-Castillo et al. 2014)): (A) it promotes neurite outgrowth via the N-syndecan receptor (Raulo et al. 1994; Kinnunen et al. 1996) or via neuroglycan C (NGC) (Nakanishi et al. 2010); (B) it interacts with the integrin αυβ3 (alpha nu beta 3) receptor, a mechanosensitive cell membrane receptor, for cell adhesion (Mikelis et al. 2009), and (C) it interacts with the low-density lipoprotein (LDL) receptor-related protein (LRP) (Kadomatsu and Muramatsu 2004). However, in none of these cases has it been established to date which is the form (PTN18 or PTN15) that interacts with those receptors; therefore, their differential interaction or affinities to these different receptors has not yet been established, which adds another level of complexity to their physiological functioning.
It has been recently proposed that PTN signaling may function through a multireceptor complex (Xu et al. 2014), combining the previously mentioned receptors and, most probably, other adaptor proteins, which interact under certain circumstances inside particular cell membrane microdomains, probably also associated with lipids in raft configuration. The latter could explain the variety of functions in different tissues, in terms of the combinatorial analysis of the elements present at each time and place.
PTN Classical Functions During Development
During development, PTN plays a role as a growth factor, signaling for cell growth, cell proliferation, and differentiation. PTN functions mainly during bone formation and chondrogenesis, as well as in organs undergoing branching morphogenesis, such as the kidney, lung, and in vascular tissue for angiogenesis (Fig. 4).
In Bone Formation and Chondrogenesis
PTN, also known as osteoblast-specific factor 1 (OSF-1), is highly expressed in fetal bone cartilage and is implicated in bone formation and remodeling (Tare et al. 2002). During the early stages of osteogenic differentiation, PTN is synthesized by osteocytes and localized at sites where new bones are formed (Imai et al. 1998; Tare et al. 2002). Therefore, based on its participation in angiogenesis as a heparin-binding angiogenic growth factor, a role in bone repair has been ascribed to PTN (Reviewed in (Lamprou et al. 2014)). Additionally, exogenous PTN, but not MK, promotes chondrogenesis in a micromass culture of chicken limb bud mesenchymal cells (Dreyfus et al. 1998). PTN promotes bone morphogenetic protein (BMP)-induced osteogenesis at a high concentration and has an opposite effect at a low concentration (Sato et al. 2002; Li et al. 2005).
Moreover, PTN can act as an inducer of hypertrophy during chondrogenic differentiation of human bone marrow stromal cells (hBMSC) (Bouderlique et al. 2014). Regarding therapy, PTN appears to mediate repair and protective processes in osteoarthritic cartilage and to be a promising factor for the treatment of osteoarthritis (Reviewed in (Mentlein 2007)).
In Kidney Development
In epithelial organogenesis, branching morphogenesis constitutes a central process, and PTN has been described as a key mesenchymally derived factor that regulates branching morphogenesis of the ureteric bud (Sakurai et al. 2001). Additionally, PTN expression is highly induced in human mesangial cells in vitro and triggers these to migrate (Martin et al. 2006).
In Lung Development
PTN has been involved, acting together with Wnt/β-catenin, for guiding the epithelial mesenchymal interactions during fibroblast and epithelial cell communication during fetal lung development (Weng et al. 2009; Weng and Liu 2010).
Function in Angiogenesis
PTN (−/−) mice displayed significantly decreased bone marrow (BM) hematopoietic stem cell (HSC) content and impaired hematopoietic regeneration following myelosuppression (Istvanffy et al. 2011). Conversely, mice lacking RPTPζ, which is inactivated by PTN, displayed significantly increased BM HSC content (Schinke et al. 2008). Therefore, PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo (Himburg et al. 2012). In addition, expression of endogenous PTN correlates with and appears to be involved in vivo in the angiogenesis of chicken embryo chorioallantoic membrane, and its action is mediated by nucleolin (Koutsioumpa et al. 2012). PTN is secreted by BM-derived endothelial cells and increased the survival of mice following radiation exposure and after myeloablative BM transplantation, mediating hematopoietic regeneration in a RAS-dependent manner (Himburg et al. 2014). Additionally, PTN acts as an angiogenesis “driver” by promoting the creation of a proangiogenic environment, migratory behavior in EC, and a proregenerative, alternative phenotype in macrophages (Palmieri et al. 2015). PTN is able to induce ex vivo angiogenesis during aging, constituting a promising therapy for inducing neovascularization in aged tissues (Besse et al. 2013).
As a Secretory Cytokine Involved in Cancer
Dissolution of cell–cell adhesive contacts and increased cell–ECM adhesion are hallmarks of the migratory and invasive phenotype of cancer cells. These changes are facilitated by growth factor binding to receptor protein tyrosine kinases (RTK). In normal cells, cell–cell adhesion molecules (CAM), including some receptor protein tyrosine phosphatases (RPTP), antagonize RTK signaling by promoting adhesion on migration. In cancer, RTK signaling is constitutive due to mutated or amplified RTK, which leads to growth factor independence or autonomy (Phillips-Mason et al. 2011).
PTN is highly expressed in different human tumors, in which it accelerates their growth and stimulates angiogenesis (Zhang et al. 2006; Perez-Pinera et al. 2008), including the following: (i) pancreatic (Yao et al. 2009, 2013), where it contributes to increased perineural invasion and poor prognosis; (ii) melanomas (Wu et al. 2005), where it is associated with its metastatic potential; (iii) in glioblastoma (Lu et al. 2005) and in astrocytomas (Peria et al. 2007), where is related with its histopathological grade; (iv) it is also a tumor growth factor for angiogenesis in some types of breast cancer (Fang et al. 1992; Wellstein et al. 1992; Czubayko et al. 1995; Chang et al. 2007); (v) for colorectal cancer, where could serve as a prognostic factor, because PTN promotes VEGF expression and cooperates with VEGF in promoting angiogenesis (Kong et al. 2012), and (vi) it is a stimulatory signal in prostate cancer (Hatziapostolou et al. 2006; Polytarchou et al. 2009; Orr et al. 2011).
Recently, Elahouel et al. (2015) demonstrated that PTN exert its action by interacting directly through its thrombospondin type-I repeat domains, with neuropilin 1 (NRP-1), which is a receptor for multiple growth factors that mediates cell motility and plays an important role in angiogenesis and tumor progression (Klagsbrun et al. 2002). Therefore, NRP-1/PTN interaction constitutes a novel mechanism for controlling the response of endothelial and tumoral cells to PTN and may explain, at least in part, how PTN contributes to tumor angiogenesis and cancer progression (Elahouel et al. 2015).
PTN as a Neuromodulatory Peptide with Multiple Neuronal Functions
In adult vertebrate CNS, PTN exerts post-developmental neurotrophic and protective effects and additionally has been involved in neurodegenerative disorders (Fig. 4). Consequently, PTN has been recently proposed as a neuromodulatory peptide in adult CNS (Gonzalez-Castillo et al. 2014).
Participates in Neurogenesis, Neural Migration, and Differentiation
PTN regulates neural stem-cell proliferation in vivo and in vitro. PTN knockout mice (PTN−/−) exhibit an increased proliferation rate of neuronal stem cells in adult mouse cerebral cortex, and exogenous PTN reduces neuronal stem-cell proliferation and promotes cell differentiation (Hienola et al. 2004). Additionally, neural migration in the rostral migratory stream is impaired in N-syndecan-null mice, one of the receptors of PTN (Hienola et al. 2006). Furthermore, PTN promotes the production of DAergic neurons from ES cell-derived, nestin-positive cells (Jung et al. 2004). Thus, PTN constitute a modulatory system that accounts for the balance between cell proliferation and differentiation in the vertebrate nervous system, which appears to be facilitated by the Brd2 antagonist mediated by PTN (Garcia-Gutierrez et al. 2014).
Contributes to Axonal and Neurite Outgrowth, Regeneration, and Neuron Survival
PTN serves as extracellular cues in axonal growth and guidance (Raulo et al. 2005), which induce neuritogenesis (Bao et al. 2005), as well as in neurite outgrowth (Kinnunen et al. 1996; Yanagisawa et al. 2010) and axonal outgrowth (Mitsiadis et al. 1995; Kadomatsu and Muramatsu 2004). In addition, it participates in dendritogenesis and synaptogenesis (Asai et al. 2009). Additionally, PTN constitutes a factor for peripheral nerve regeneration under pathological conditions (Blondet et al. 2006), which reverses the inhibition of neural regeneration elicited by chondroitin sulfate glycosaminoglycans (GAG) (Paveliev et al. 2016).
Is Involved in Hippocampal Memory and Learning
In the hippocampus, PTN expression is induced by long-term potentiation (LTP) (Lauri et al. 1996) and is involved in the regulation of synaptic plasticity (Lauri et al. 1998). Additionally, PTN inhibited hippocampal LTP induced by high-frequency stimulation (HFS) (del Olmo et al. 2009). Furthermore, PTN (−/−) exhibited enhanced hippocampal LTP (Amet et al. 2001), and transgenic mice overexpressing PTN have attenuated hippocampal LTP (Pavlov et al. 2002) by enhancing hippocampal GABAergic inhibition (Pavlov et al. 2006). Additionally, two knockout mice for receptors for PTN exhibited alterations in hippocampus-dependent memory. Syndecan-3-deficient mice exhibit enhanced LTP and impaired hippocampus-dependent memory (Kaksonen et al. 2002). Also, RPTPζ-deficient mice exhibit impairments in hippocampus-dependent contextual fear memory because of abnormal tyrosine phosphorylation of p190 RhoGAP, a GTPase-activating protein (GAP) for Rho GTPase (Tamura et al. 2006); therefore, PTN is able to modulate LTP by activity-dependent plasticity. Recently, it has been demonstrated that environmental enrichment increases PTN expression, which correlates with an improvement in cognition and brain functional markers in young senescence-accelerated prone mice (SAMP8) (Grinan-Ferre et al. 2016).
Modulates Nociceptive Transmission
PTN (−/−) mice exhibit a disruption of spinal nociceptive transmission in the control of pain processing (Gramage and Herradon 2010), potentiating analgesia caused by stimulation of α2-adrenoceptors (Vicente-Rodriguez et al. 2013), which is not altered in MK (−/−) mice (Gramage et al. 2012).
As a Secretory Cytokine Involved in Drug Addiction
PTN expression is increased in response to chronic drug consumption (Mailleux et al. 1994; Le Greves 2005) and is highly upregulated in different brain areas after administration of different drugs of abuse (Reviewed in (Herradon and Perez-Garcia 2014)). PTN deficiency confers vulnerability to developing neurodegenerative processes induced by drugs of abuse in humans. The genetic deletion of pleiotrophin (PTN−/−) shows enhanced amphetamine neurotoxicity (Gramage et al. 2010). Moreover, in mice with transgenic PTN overexpression, amphetamine caused an enhanced loss of striatal dopaminergic terminals in the striatum (Vicente-Rodriguez et al. 2016). PTN prevent the neurotoxic effects of amphetamine on nigrostriatal pathways, and endogenous PTN also limits amphetamine reward (Vicente-Rodriguez et al. 2016). In fact, there are several patents in existence for the use of PTN, as well as MK, in the treatment and diagnosis of neuropsychiatric disorders with a focus on neurotoxicity, neurodegeneration, and substance use disorders (Reviewed in (Alguacil and Herradon 2015)).
Participates in Neuroprotective Effect After Injury and Has Been Involved in Neurodegenerative Disorders
An increase in the expression of PTN in reactive astrocytes following hippocampal neuronal injury has been described (Takeda et al. 1995; Poulsen et al. 2000) and also in astrocytes after cryoinjury in mouse brain, providing a supportive environment for regenerating axons (Iseki et al. 2002). It has additionally been implicated in the denervated striatum of levodopa-treated rats (Ferrario et al. 2004), being involved in vitro in the survival of dopaminergic neurons (Marchionini et al. 2007) and as a potential neuroprotective agent for reconstruction of the DA nigrostriatal pathway (Gombash et al. 2014). Additionally, PTN promoted the proliferation of microglia and stimulated the secretion of neurotrophic factors by acting through the ERK1/ERK2 pathway after ischemia/reperfusion injury (Miao et al. 2012). Taken together, this evidence has led to the proposal, by several authors, that PTN possesses a neuroprotective effect.
In addition, PTN has been involved in neurodegenerative disorders. It has been reported as expressed in striatal interneurons (Taravini et al. 2005) and promoted functional recovery when PTN-treated donor cells were grafted into the striata of hemi-parkinsonian rats (Hida et al. 2007). In addition, PTN is upregulated in the degenerating substantia nigra of patients with Parkinson disease (PD) (Marchionini et al. 2007). Therefore, blocking RPTPζ/β has been proposed as a potential therapeutic strategy for the treatment of PD (Herradon et al. 2009), mainly because PTN overexpression provides trophic support to DAergic neurons in parkinsonian rats (Taravini et al. 2011).
PTN has been reported as highly expressed in amyloid-beta deposits in Alzheimer and Down brains (Wisniewski et al. 1996), although, to our knowledge, no one had reported similar results since. More recently, PTN has been involved in the development of neurodegenerative changes during aging (Grinan-Ferre et al. 2016).
PleioTrophiN (PTN) is a secreted cell-signaling cytokine that acts as a growth factor associated with the ExtraCellular Matrix (ECM), which is highly conserved throughout evolution. It is a relatively small peptide (136 residues and 18 KDa in its soluble form) that can additionally be fragmented by proteolytic cleavage in at least five different functional peptides. This implies the need for reinterpreting, or at least reconsidering, practically all of the results reported to date for PTN functions and effects. Also, it possesses several functional domains that can differentially interact with diverse receptors, and even with different receptor complexes. It is highly expressed during development in the Central (CNS) and Peripheral Nervous Systems (PNS), as well as in organs undergoing branching morphogenesis (lung, kidney, and vascular tissue), and during bone formation and chondrogenesis. It is generally located in the basement membrane of the developing epithelium and in mesenchymal tissues undergoing remodeling. Although during the adult stage its expression is confined mainly to CNS, its expression can be highly induced in response to damage in certain pathologies (such as fibrogenesis, neovascularization, and neuronal injury), and it is directly involved in carcinogenesis, where it accelerates tumor growth and stimulates angiogenesis. By its pleiad of actions such as soluble cytokines, its versatile and differential involvement in ECM cell – cell interactions, as well as their large number of functions in different tissues, PTN results in an extremely interesting modulatory peptide.
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