Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease

Kanno, Hiroshi; Yoshizumi, Tetsuya; Shinonaga, Masamichi; Kubo, Atsuhiko; Murata, Hidetoshi; Yao, Masahiro

doi:10.1007/s11060-020-03506-8

Cited by 10 publications

(12 citation statements)

References 41 publications

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“…Collectively, these data point to the existence of a signalling axis formed by VHL-EPOR/JAK/SOCS/STAT3 which may play important roles in supporting cancer cells proliferation. In this direction, it is interesting that recent work from Bento et al where pVHL was demonstrated to also regulate JAK2/STAT3 signalling pathway in hemangioblastoma cells [ 102 ].…”

Section: Introductionmentioning

confidence: 99%

The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer

2020

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The von Hippel–Lindau protein (pVHL) is a tumour suppressor mainly known for its role as master regulator of hypoxia-inducible factor (HIF) activity. Functional inactivation of pVHL is causative of the von Hippel–Lindau disease, an inherited predisposition to develop different cancers. Due to its impact on human health, pVHL has been widely studied in the last few decades. However, investigations mostly focus on its role in degrading HIFs, whereas alternative pVHL protein–protein interactions and functions are insistently surfacing in the literature. In this review, we analyse these almost neglected functions by dissecting specific conditions in which pVHL is proposed to have differential roles in promoting cancer. We reviewed its role in regulating phosphorylation as a number of works suggest pVHL to act as an inhibitor by either degrading or promoting downregulation of specific kinases. Further, we summarize hypoxia-dependent and -independent pVHL interactions with multiple protein partners and discuss their implications in tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer

2020

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“…The discovery of the SOCS family began in 1995 with the isolation of a novel cytokine-inducible Src homology 2 (SH2)-containing protein (CIS) as an early gene induced by IL-2, IL-3, and erythropoietin (EPO) [ 13 ]. Subsequently, an SH2 domain–containing protein that inhibits IL-6-induced macrophage differentiation was identified in 1997 and named SOCS1 [ 14 , 15 , 16 ]. Furthermore, database searches of similar amino acid sequences predicted from SOCS1 revealed that at least 20 proteins from mice and humans share sequence homology within a 40-residue C-terminal motif called the SOCS box.…”

Section: Characteristics Of Socs Proteins and Their Roles In Neuronal...mentioning

confidence: 99%

“…The VHL forms a complex (VBC-Cul2/E3 complex) with Elongin B and C, Cullin2, and Rbx1, which acts as an E3 ligase. After the ubiquitination of JAK2, its degradation by proteasome 26S, followed by the suppression of downstream STAT expression, may affect bHLH-type transcription factors, in turn affecting the Notch signaling and STAT/Smad pathways [ 13 , 14 , 147 , 148 ]. VBC-Cul2/E3 complexes ubiquitinate HIF-1α for proteasomal 26S degradation, followed by the activation of downstream factors of HIF-1α.…”

Section: Characteristics Of Vhl Proteins and Their Roles In Neuronal ...mentioning

confidence: 99%

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development

Kanno

Matsumoto

Yoshizumi

et al. 2023

IJMS

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The basic helix–loop–helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin–proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin–proteasome system but also act directly on JAKs to suppress the Janus kinase–signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor–vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.

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“…VHL-JAK-STAT signaling plays alternative pathways in hemangioblastoma to supplement VHL-hypoxia-inducible factor (HIF) pathway. 35 Jade-1 is another tumor-suppressor protein associated with histone acetyltransferase (HAT) activity and stabilized by VHL; its destabilization contributes to cancer. 36 Independent of HIF pathway, inactivation of m 6 A ribonucleic acid (RNA) demethylase Fat mass and obesity-associated protein in the presence of VHL loss reduces tumor cells growth.…”

Section: Figure 5 Hemangioblastoma In Vhl (Hande Staining) the Tumor ...mentioning

confidence: 99%

Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review

et al. 2021

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Hereditary cancer predisposition syndromes (HCS) become more recognizable as the knowledge about them expands, and genetic testing becomes more affordable. In this review, we discussed the known HCS that predispose to central and peripheral nervous system tumors. Different genetic phenomena were highlighted, and the important cellular biological alterations were summarized. Genetic mosaicism and germline mutations are features of HCS, and recently, they were described in normal population and as modifiers for the genetic landscape of sporadic tumors. Description of the tumors arising in these conditions was augmented by representative cases explaining the main pathological findings. Clinical spectrum of the syndromes and diagnostic criteria were tabled to outline their role in defining these disorders. Interestingly, precision medicine has found its way to help these groups of patients by offering targeted preventive measures. Understanding the signaling pathway alteration of mammalian target of rapamycin (mTOR) in tuberous sclerosis helped introducing mTOR inhibitors as a prophylactic treatment in these patients. More research to define the germline genetic alterations and resulting cellular signaling perturbations is needed for effective risk-reducing interventions beyond prophylactic surgeries.

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Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease

Cited by 10 publications

References 41 publications

The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer

The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development

Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review

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