Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase

Su, Chih-Hao; Chen, Ming-Fong; Lan, Keng‐Hsin; Li, Chung–Pin; Chao, Yee; Lin, Hsin‐Hung; Lee, Shou‐Dong; Lee, Wei-Ping

doi:10.1016/j.cellsig.2011.06.018

Cited by 50 publications

(29 citation statements)

References 28 publications

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“…In fact, depletion of CHIP did not influence the protein level of PDK1, AKT, or mTOR; also, the level of the chaperone Hsp90 remained unchanged in human embryonic kidney (HEK293) cells (Figure S2E). However, it increased AKT kinase phosphorylation in flies (S505, p-AKT) and human cells (S473, p-AKT) (Figures 1J and 1K), providing further evidence for increased insulin signaling upon depletion of CHIP (Su et al., 2011). Collectively, these results suggest that CHIP provides a conserved role in the regulation of IIS activity.…”

Section: Resultsmentioning

confidence: 57%

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

Tawo

Pokrzywa

Kevei

et al. 2017

Cell

113

149

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SummaryAging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging.

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Section: Resultsmentioning

confidence: 57%

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

Tawo

Pokrzywa

Kevei

et al. 2017

Cell

113

149

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“…To detect the free ␤-catenin gets by E3s have been reported previously. For example, Thr-308 and Ser-473 phosphorylation could activate Akt, while the E3 ubiquitin ligase CHIP promotes the ubiquitination and degradation of such phosphorylated Akt only, therefore inhibiting Akt signaling (39). Both E3 ubiquitin ligases Fbw7 and MuRF1 could target activated phospho-c-Jun for ubiquitination and degradation, effectively inhibiting the Jun N-terminal protein kinase (JNK) signaling pathway (19,27).…”

Section: Itch Is a Dvl-binding Proteinmentioning

confidence: 99%

The E3 Ubiquitin Ligase ITCH Negatively Regulates Canonical Wnt Signaling by Targeting Dishevelled Protein

Wei

Wang

et al. 2012

Molecular and Cellular Biology

126

142

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“…Increased evidence showed that CHIP not only modulates misfolded proteins but also regulates pathophysiological processes. CHIP is associated with many tumor-related proteins, such as ErbB2 [10], c-Met[11], SRC-3[12], NF-κB[13], AKT[14], PTEN[15] and p53[16]. The up-regulation of CHIP could inhibit tumor growth and metastasis, and its levels were negatively correlated with the malignancy of human breast or gastric tumors.…”

Section: Introductionmentioning

confidence: 99%

CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

Wang

Yang²,

et al. 2014

Oncotarget

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Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer.

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Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase

Cited by 50 publications

References 28 publications

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover

The E3 Ubiquitin Ligase ITCH Negatively Regulates Canonical Wnt Signaling by Targeting Dishevelled Protein

CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

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