Post-translational regulation of PTEN

Wang, X; Jiang, Xuejun

doi:10.1038/onc.2008.242

Cited by 85 publications

(75 citation statements)

References 72 publications

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“…It can occur via many mechanisms, including genetic alterations, such as gene mutations or deletions, epigenetic events that lead to gene silencing, and/or proteasomal degradation, as shown, for example, for p53, PTEN, and NF1 (56,87,89). Our findings indicate that ubiquitin-proteasome-mediated degradation of Dok-1 is a key mechanism by which OTKs trigger Dok-1 "inactivation."…”

Section: Discussionmentioning

confidence: 73%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

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Section: Discussionmentioning

confidence: 73%

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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“…The cellular functions of PTEN include regulation of proliferation, cell growth, migration, genomic stability, and stem cell self-renewal (Wang and Jiang, 2008). PTEN activity can be regulated by mutations, epigenetic silencing, transcriptional repression, aberrant protein localization, and post-translational modifications (Wang and Jiang, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…PTEN is one of the critical negative regulators of the PI3K-Akt signaling pathway and is considered a tumor suppressor gene (Chu and Tarnawski, 2004;Wang and Jiang, 2008). The cellular functions of PTEN include regulation of proliferation, cell growth, migration, genomic stability, and stem cell self-renewal (Wang and Jiang, 2008).…”

Section: Discussionmentioning

confidence: 99%

A microRNA-152 that targets the phosphatase and tensin homolog to inhibit low oxygen induced-apoptosis in human brain microvascular endothelial cells

Cao

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Brain damage caused by perinatal asphyxia is dangerous for neonatal infants, but the mechanism by which it occurs remains elusive. In this study, microRNA-152 (miR-152) expression was induced by low oxygen levels in rat models of hypoxia brain damage, as well as in human brain microvascular endothelial cells (HBMECs) cultured in vitro. Analysis of the sequence of miR-152 revealed that the phosphatase and tensin homolog gene (PTEN) is probably the target of miR-152 both in humans and rats. When HBMECs were transfected with miR-152 mimics, PTEN expression was inhibited at both the mRNA and protein levels. Moreover, transfection with the miR-152 mimic also inhibited apoptosis induced by hypoxia. Furthermore, expression of the pro-apoptotic gene Bax was downregulated while the anti-apoptotic gene Bcl2 was upregulated after miR-152 mimic transfection. Taken together, these results indicate that miR-152 induced by hypoxia suppresses cell apoptosis and acts as a protective factor during hypoxia by repressing PTEN.

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“…It has previously been shown to be tightly regulated both at the transcriptional and post-translational levels (13,14). PTEN is heavily regulated by phosphorylation, S-nitrosylation, acetylation, and oxidation at the posttranslational level (15). In addition, ubiquitination plays one of the most significant roles in the regulation of PTEN degradation and compartmentalization (16).…”

Section: Pten (Phosphatase and Tensin Homologue Deleted On Chromosomementioning

confidence: 99%

The Chaperone-assisted E3 Ligase C Terminus of Hsc70-interacting Protein (CHIP) Targets PTEN for Proteasomal Degradation

Ahmed

Deb

Paul

et al. 2012

Journal of Biological Chemistry

140

138

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Background: PTEN is targeted by multiple E3 ligases but that does not clearly decipher the rigid control of its level and activity. Results: CHIP interacts with PTEN and promotes its proteasomal degradation. Conclusion: CHIP acts as a bridge between the chaperone system and the degradation machinery for PTEN. Significance: Stabilization of PTEN by targeting CHIP can be a novel therapeutic approach in cancer regulation.

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Post-translational regulation of PTEN

Cited by 85 publications

References 72 publications

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

A microRNA-152 that targets the phosphatase and tensin homolog to inhibit low oxygen induced-apoptosis in human brain microvascular endothelial cells

The Chaperone-assisted E3 Ligase C Terminus of Hsc70-interacting Protein (CHIP) Targets PTEN for Proteasomal Degradation

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