Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

Xu, Chunmei; Zhu, Shunying; Wu, Mingyuan; Wang, Han; Yu, Yan

doi:10.1248/bpb.b13-00845

Cited by 71 publications

(66 citation statements)

References 88 publications

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“…These data were somewhat unexpected given PTN's reported role in developmental angiogenesis [13], [14], the association between neurogenesis and vasculogenesis [58], [59], and the hypothesized impact of vascular status on progenitor cell proliferation and neuronal differentiation in both developmental and pathological states [60]. The homologous protein midkine has many of the same development effects as PTN [61], suggesting that compensatory effects of midkine are a possible explanation for the preservation of vascular development in the PTN KO brain. Alternatively, EC neuronal abnormalities in the KOs could be driven by subtle, transitory vascular defects or be independent of cerebral vascular status.…”

Section: Discussionmentioning

confidence: 98%

Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

et al. 2014

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Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.

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Section: Discussionmentioning

confidence: 98%

Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

et al. 2014

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“…The extracellular region of PTPRZ is responsible for its binding with various secretory factors (such as PTN, MK, IL-34, and basic fibroblast growth factor) (20,23,24,33), extracellular matrix proteins (tenascin-C and -R) (34), and cell adhesion molecules (Nr-CAM, L1/Ng-CAM, F3/contactin, NCAM, and TAG1/axonin-1) (35). Among these molecules, PTN, MK, and IL-34 have been shown to function as inhibitory ligands against the PTPase activity of PTPRZ receptor isoforms (12,20,21,23,24).…”

Section: Discussionmentioning

confidence: 99%

Role of Chondroitin Sulfate (CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity

Kuboyama

Fujikawa

Suzuki

et al. 2016

Journal of Biological Chemistry

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Protein-tyrosine phosphatase receptor type Z (PTPRZ) is predominantly expressed in the developing brain as a CS proteoglycan. PTPRZ has long (PTPRZ-A) and short type (PTPRZ-B) receptor forms by alternative splicing. The extracellular CS moiety of PTPRZ is required for high-affinity binding to inhibitory ligands, such as pleiotrophin (PTN), midkine, and interleukin-34; however, its functional significance in regulating PTPRZ activity remains obscure. We herein found that protein expression of CS-modified PTPRZ-A began earlier, peaking at approximately postnatal days 5-10 (P5-P10), and then that of PTN peaked at P10 at the developmental stage corresponding to myelination onset in the mouse brain. Ptn-deficient mice consistently showed a later onset of the expression of myelin basic protein, a major component of the myelin sheath, than wild-type mice. Upon ligand application, PTPRZ-A/B in cultured oligodendrocyte precursor cells exhibited punctate localization on the cell surface instead of diffuse distribution, causing the inactivation of PTPRZ and oligodendrocyte differentiation. The same effect was observed with the removal of CS chains with chondroitinase ABC but not polyclonal antibodies against the extracellular domain of PTPRZ. These results indicate that the negatively charged CS moiety prevents PTPRZ from spontaneously clustering and that the positively charged ligand PTN induces PTPRZ clustering, potentially by neutralizing electrostatic repulsion between CS chains. Taken altogether, these data indicate that PTN-PTPRZ-A signaling controls the timing of oligodendrocyte precursor cell differentiation in vivo, in which the CS moiety of PTPRZ receptors maintains them in a monomeric active state until its ligand binding.Myelination is an essential feature of the vertebrate nervous system that electrically insulates axons, thereby enabling the salutatory transmission of nerve impulses. Oligodendrocyte precursor cells (OPCs) 2 are the principal source of myelinating oligodendrocytes (1). Previous studies reported that protein tyrosine phosphorylation is crucially involved in the signal transduction mechanism for OPC differentiation into mature oligodendrocytes and myelin formation. FYN kinase in the Src tyrosine kinase family is the most prominent member involved in OPC differentiation and myelin formation (2). FYN activity is up-regulated during oligodendrocyte differentiation (3, 4), and Fyn-knock-out mice exhibit hypomyelination in the brain (5, 6). FYN phosphorylates p190 RhoGAP, a GTPase-activating protein (GAP) for Rho GTPase, to suppress Rho/ROCK, resulting in the maturation of oligodendrocytes and myelination (7,8).PTPRZ is the most abundant receptor-type protein-tyrosine phosphatase (RPTP) in OPCs (9, 10). PTPRZ dephosphorylates p190 RhoGAP, thereby acting as a counterpart of FYN (11,12). The amounts of myelin basic protein (MBP) and myelinated axons in the brain at postnatal day 10, when myelination occurs, are significantly higher in Ptprz-deficient mice than in wildtype animals, indicating a suppre...

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“…Both midkine and pleiotrophin have diverse functions, such as angiogenesis, oncogenesis and inflammation. The high expression levels of midkine and pleiotrophin in many types of cancers make them excellent as biomarkers and therapeutic targets for cancer [23, 24]. Up to date, the evidence of pleiotrophin in autoimmune diseases is also very limited.…”

Section: Introductionmentioning

confidence: 99%

Elevated plasma midkine and pleiotrophin levels in patients with systemic lupus erythematosus

Yuan

Pan

et al. 2016

Oncotarget

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Emerging evidence suggests that two heparin-binding growth factor, midkine and pleiotrophin are implicated in the pathogenesis of autoimmune diseases including SLE. To investigate the plasma midkine and pleiotrophin levels in SLE patients, as well as their correlation with major clinical parameters and interleukin-17 (IL-17) level in SLE, 83 SLE patients and 123 controls including 20 rheumatoid arthritis (RA) patients, 21 Sjögren's syndrome (SS) patients and 82 healthy controls (HCs) were recruited. Plasma midkine, pleiotrophin and IL-17 levels were detected by ELISA. Midkine and pleiotrophin levels were significantly higher in SLE, RA and SS patients compared with HCs (all P < 0.05). There were significantly lower midkine and pleiotrophin levels in SLE compared to SS (P < 0.05 and P < 0.01, respectively). No significant differences in midkine and pleiotrophin levels were found between SLE and RA (P = 0.240 and P = 0.074, respectively). Both plasma midkine and pleiotrophin levels were associated with rash and anti-SSA in SLE. In addition, both midkine and pleiotrophin levels were positively associated with IL-17 level in SLE (both P < 0.001). Area under curve (AUC) of the receiver operating characteristic (ROC) curve for midkine and pleiotrophin were 0.606 (0.527–0.681) and 0.605 (0.526–0.680) respectively. In conclusion, elevated plasma midkine and pleiotrophin levels and their associations with rash, anti-SSA and IL-17 in SLE patients suggest their involvement in this disease.

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Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

Cited by 71 publications

References 88 publications

Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

Role of Chondroitin Sulfate (CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity

Elevated plasma midkine and pleiotrophin levels in patients with systemic lupus erythematosus

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