Sushi repeat-containing protein X-linked 2 promotes angiogenesis through the urokinase-type plasminogen activator receptor dependent integrin αvβ3/focal adhesion kinase pathways

Liu, Kuiliang; Fan, Jianghao; Wu, Jing

doi:10.5582/ddt.2017.01017

Cited by 20 publications

(16 citation statements)

References 20 publications

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“…Little is known about uPAR interaction with αvβ3 integrin although there are some indications that αvβ3 integrin is implicated in regulatory functions mediated by the uPAR system. In this respect, uPAR activation by proteoglycan, a major component of ECM, promotes the acquisition of an angiogenic profile by human umbilical vein endothelial cells (HUVEC) through the involvement of αvβ3 integrin [75]. In addition, in VEGF-stimulated HUVEC, inhibiting uPAR blunts αvβ3 integrin activity thus preventing the acquisition of an angiogenic phenotype [33].…”

Section: Upar-co-receptor Interactionmentioning

confidence: 99%

“…Among them, the activation of the focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase that plays a critical role in integrin-mediated signal transduction, represents a priming step in inducing kinase-mediated cascades including the Janus kinase 1 (JAK1), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Ras/mitogen activated protein kinase (MAPK) and Rac1/MAPK pathways, which are involved in directing cellular responses to a wide array of stimuli by increasing the expression of sets of pro-angiogenic and inflammatory genes [106]. For instance, the cooperation of uPAR with the integrin/FAK pathway promotes endothelial cell proliferation and migration by specific proteoglycans, which have important effects on various aspects of angiogenesis [75]. Additionally, FAK recruits members of the proto-oncogene tyrosine-protein kinase Src family to enhance the activity of VEGFR2 that, in turn, induces angiogenic profiles by activating the PI3K/AKT, MAPK and JAK1 pathways [107,108].…”

Section: Mechanisms Of Upar Signalingmentioning

confidence: 99%

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The uPAR System as a Potential Therapeutic Target in the Diseased Eye

Cammalleri

Monte

Pavone

et al. 2019

Cells

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Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence of photoreceptor degeneration in inherited eye diseases with a major inflammatory component, but without angiogenic profile. Among the pathways with high impact on vascular/degenerative diseases of the eye, a central role is played by a system formed by the ligand urokinase-type plasminogen activator (uPA) and its receptor uPAR. The uPAR system, although extensively investigated in tumors, still remains a key issue in vascular diseases of the eye and even less studied in inherited retinal pathologies such as retinitis pigmantosa (RP). Its spectrum of action has been extended far beyond a classical pro-angiogenic function and has emerged as a central actor in inflammation. Preclinical studies in more prevalent eye diseases characterized by neovascular formation, as in retinopathy of prematurity, wet macular degeneration and rubeosis iridis or vasopermeability excess as in diabetic retinopathy, suggest a critical role of increased uPAR signaling indicating the potentiality of its modulation to counteract neovessel formation and microvascular dysfunction. The additional observation that the uPAR system plays a major role in RP by limiting the inflammatory cascade triggered by rod degeneration rises further questions about its role in the diseased eye.

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Section: Upar-co-receptor Interactionmentioning

confidence: 99%

Section: Mechanisms Of Upar Signalingmentioning

confidence: 99%

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

Cammalleri

Monte

Pavone

et al. 2019

Cells

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“…The function of SRPX2 in cancer cells requires interaction with uPAR on the cell surface and engagement of membrane co‐receptors, such as α v β3 integrin and PDGFRβ receptors. This results in intracellular activation of the P12k/Akt, Ras/MAPK, and P‐FAK/Akt pathways, eventually activating MMP2 and MMP9 matrix metalloproteinases (Lin et al, ; Liu, Fan, & Wu, ; Tang et al, ; Yamada et al, ). Expression of SRPX2 in colorectal cancer is regulated by nonCpG island promoter hypomethylation and post‐transcriptionally by miR‐149 (Øster et al, ).…”

Section: Introductionmentioning

confidence: 99%

Sushi repeat‐containing protein X‐linked 2: A novel phylogenetically conserved hypothalamo‐pituitary protein

Anwer

Bolkvadze

Ndode-Ekane

et al. 2018

J of Comparative Neurology

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Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel protein associated with language development, synaptic plasticity, tissue remodeling, and angiogenesis. We investigated the expression and spatial localization of SRPX2 in normal mouse, rat, monkey, and human brain using in situ hybridization and immunohistochemistry. Antibody specificity was determined using in vitro siRNA based silencing of SRPX2. Cell type-specific expression was verified by double-labeling with oxytocin or vasopressin. Western blot was used to detect SRPX2 protein in rat and human plasma and cerebrospinal fluid. Unexpectedly, SRPX2 mRNA expression levels were strikingly higher in the hypothalamus as compared to the cortex. All SRPX2 immunoreactive (ir) neurons were localized in the hypothalamic paraventricular, periventricular, and supraoptic nuclei in mouse, rat, monkey, and human brain. SRPX2 colocalized with vasopressin or oxytocin in paraventricular and supraoptic neurons. Hypothalamic SRPX2-ir positive neurons gave origin to dense projections traveling ventrally and caudally toward the hypophysis. Intense axonal varicosities and terminal arborizations were identified in the rat and human neurohypophysis. SRPX2-ir cells were also found in the adenohypophysis. Light SRPX2-ir projections were observed in the dorsal and ventral raphe, locus coeruleus, and the nucleus of the solitary tract in mouse, rat and monkey. SRPX2 protein was also detected in plasma and CSF. Our data revealed intense phylogenetically conserved expression of SRPX2 protein in distinct hypothalamic nuclei and the hypophysis, suggesting its active role in the hypothalamo-pituitary axis. The presence of SRPX2 protein in the plasma and CSF suggests that some of its functions depend on secretion into body fluids.

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“…The gene that encodes the HGF interactor SRPX2 (Figure 4E) proved to be subjected to a high intensity phenomenon of intron retention, specifically in melanoma samples (Figure 5). SRPX2 is a synaptogenic factor that critically contributes to the pathogenesis of language disorders [80,81,82], while it is also implicated in cell adhesion, migration and invasion [83,84,85], angiogenesis [86,87], resistance to therapy and epithelial to mesenchymal transition [88]. As indicated by the amplification profiles of the expected 178 bp long PCR product, in contrast to BCC and SCC (Figure 5A), melanoma samples proved to lack detectable levels of SRPX2 regular gene expression (Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients

Giannopoulou

Konstantakou

Velentzas

et al. 2019

IJMS

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Background: Skin cancer represents the most common human malignancy, and it includes BCC, SCC, and melanoma. Since melanoma is one of the most aggressive types of cancer, we have herein attempted to develop a gene-specific intron retention signature that can distinguish BCC and SCC from melanoma biopsy tumors. Methods: Intron retention events were examined through RT-sqPCR protocols, using total RNA preparations derived from BCC, SCC, and melanoma Greek biopsy specimens. Intron-hosted miRNA species and their target transcripts were predicted via the miRbase and miRDB bioinformatics platforms, respectively. Ιntronic ORFs were recognized through the ORF Finder application. Generation and visualization of protein interactomes were achieved by the IntAct and Cytoscape softwares, while tertiary protein structures were produced by using the I-TASSER online server. Results: c-MYC and Sestrin-1 genes proved to undergo intron retention specifically in melanoma. Interaction maps of proteins encoded by genes being potentially targeted by retained intron-accommodated miRNAs were generated and SRPX2 was additionally delivered to our melanoma-specific signature. Novel ORFs were identified in MCT4 and Sestrin-1 introns, with potentially critical roles in melanoma development. Conclusions: The property of c-MYC, Sestrin-1, and SRPX2 genes to retain specific introns could be clinically used to molecularly differentiate non-melanoma from melanoma tumors.

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Sushi repeat-containing protein X-linked 2 promotes angiogenesis through the urokinase-type plasminogen activator receptor dependent integrin αvβ3/focal adhesion kinase pathways

Cited by 20 publications

References 20 publications

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

Sushi repeat‐containing protein X‐linked 2: A novel phylogenetically conserved hypothalamo‐pituitary protein

Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients

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