14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

Gómez-Suárez, Mauricio; Gutiérrez-Martínez, Itzel Zenidel; Hernández-Trejo, José Antonio; Hernández‐Ruiz, Marcela; Suárez-Pérez, Dimelza; Candelario, Aurora; Kamekura, Ryuta; Medina-Contreras, Óscar; Schnoor, Michael; Ortiz-Navarrete, Vianney; Villegas‐Sepúlveda, Nicolás; Parkos, Charles A.; Nusrat, Asma; Nava, Porfirio

doi:10.1038/cdd.2015.163

Cited by 52 publications

(41 citation statements)

References 69 publications

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“…Since our data showed that CUEDC2 protected LDHA from proteasome degradation without direct interaction with LDHA, we crossly compared the lists of candidate proteins binding to LDHA and the CUEDC2‐interacted ones, leading to the discovery of 14‐3‐3ζ as an effecter of CUEDC2 in regulation of LDHA protein stability. 14‐3‐3 family proteins, constituted of seven conserved members in eukaryotic cells, are well known for promoting cell survival by binding to a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors . Our further results proved that 14‐3‐3ζ was the direct mediator of LDHA activation and metabolic reprogramming triggered by CUEDC2 in cancer cells.…”

Section: Discussionsupporting

confidence: 58%

CUE domain‐containing protein 2 promotes the Warburg effect and tumorigenesis

et al. 2017

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Cancer progression depends on cellular metabolic reprogramming as both direct and indirect consequence of oncogenic lesions; however, the underlying mechanisms are still poorly understood. Here, we report that CUEDC2 (CUE domain-containing protein 2) plays a vital role in facilitating aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we show that CUEDC2 upregulates the two key glycolytic proteins GLUT3 and LDHA via interacting with the glucocorticoid receptor (GR) or 14-3-3ζ, respectively. We further demonstrate that enhanced aerobic glycolysis is essential for the role of CUEDC2 to drive cancer progression. Moreover, using tissue microarray analysis, we show a correlation between the aberrant expression of CUEDC2, and GLUT3 and LDHA in clinical HCC samples, further demonstrating a link between CUEDC2 and the Warburg effect during cancer development. Taken together, our findings reveal a previously unappreciated function of CUEDC2 in cancer cell metabolism and tumorigenesis, illustrating how close oncogenic lesions are intertwined with metabolic alterations promoting cancer progression.

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Section: Discussionsupporting

confidence: 58%

CUE domain‐containing protein 2 promotes the Warburg effect and tumorigenesis

et al. 2017

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“…Therefore, SRARP expression is associated with transcriptional regulation, small GTPases, and chaperone proteins in both breast and prostate cancers; however, SRARP also correlates with unique pathways in each malignancy. Of note, 14‐3‐3 is known to regulate both the Akt and ERK signaling pathways at multiple levels (Ajjappala et al ., ; Gomez‐Suarez et al ., ; Mhawech, ). Collectively, these findings suggest that SRARP and HSPB7 interactions with 14‐3‐3 protein and the regulation of Akt and ERK may be interconnected.…”

Section: Discussionmentioning

confidence: 97%

SRARP and HSPB7 are epigenetically regulated gene pairs that function as tumor suppressors and predict clinical outcome in malignancies

Naderi

2018

Molecular Oncology

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Deletions of chromosome 1p36 are common in cancers; however, despite extensive studies, there has been limited success for discovering candidate tumor suppressors in this region. SRARP has recently been identified as a novel corepressor of the androgen receptor (AR) and is located on chromosome 1p36. Here, bioinformatics analysis of large tumor datasets was performed to study SRARP and its gene pair, HSPB7. In addition, using cancer cell lines, mechanisms of SRARP and HSPB7 regulation and their molecular functions were investigated. This study demonstrated that SRARP and HSPB7 are a gene pair located 5.2 kb apart on 1p36.13 and are inactivated by deletions and epigenetic silencing in malignancies. Importantly, SRARP and HSPB7 have tumor suppressor functions in clonogenicity and cell viability associated with the downregulation of Akt and ERK. SRARP expression is inversely correlated with genes that promote cell proliferation and signal transduction, which supports its functions as a tumor suppressor. In addition, AR exerts dual regulatory effects on SRARP, and although an increased AR activity suppresses SRARP transcription, a minimum level of AR activity is required to maintain baseline SRARP expression in AR+ cancer cells. Furthermore, as observed with SRARP, HSPB7 interacts with the 14‐3‐3 protein, presenting a shared molecular feature between SRARP and HSPB7. Of note, genome‐ and epigenome‐wide associations of SRARP and HSPB7 with survival strongly support their tumor suppressor functions. In particular, DNA hypermethylation, lower expression, somatic mutations, and lower copy numbers of SRARP are associated with worse cancer outcome. Moreover, DNA hypermethylation and lower expression of SRARP in normal adjacent tissues predict poor survival, suggesting that SRARP inactivation is an early event in carcinogenesis. In summary, SRARP and HSPB7 are tumor suppressors that are commonly inactivated in malignancies. SRARP inactivation is an early event in carcinogenesis that is strongly associated with worse survival, presenting potential translational applications.

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“…Interestingly, increased proliferation as observed in untreated cortactin KO colon epithelium ( Figure 1f) was no longer observed after DSS treatment (see Supplementary Figure S3). This finding suggests that this potential protective mechanism under basal conditions 18 is no longer active under inflammatory conditions, which could contribute to the more severe phenotype in cortactin KO mice.…”

Section: Cortactin Deficiency Aggravates Experimental Colitismentioning

confidence: 96%

Cortactin deficiency causes increased RhoA/ROCK1-dependent actomyosin contractility, intestinal epithelial barrier dysfunction, and disproportionately severe DSS-induced colitis

et al. 2017

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The intestinal epithelium constitutes a first line of defense of the innate immune system. Epithelial dysfunction is a hallmark of intestinal disorders such as inflammatory bowel diseases (IBDs). The actin cytoskeleton controls epithelial barrier integrity but the function of actin regulators such as cortactin is poorly understood. Given that cortactin controls endothelial permeability, we hypothesized that cortactin is also important for epithelial barrier regulation. We found increased permeability in the colon of cortactin-KO mice that was accompanied by reduced levels of ZO-1, claudin-1, and E-cadherin. By contrast, claudin-2 was upregulated. Cortactin deficiency increased RhoA/ROCK1-dependent actomyosin contractility, and inhibition of ROCK1 rescued the barrier defect. Interestingly, cortactin deficiency caused increased epithelial proliferation without affecting apoptosis. KO mice did not develop spontaneous colitis, but were more susceptible to dextran sulfate sodium colitis and showed severe colon tissue damage and edema formation. KO mice with colitis displayed strong mucus deposition and goblet cell depletion. In healthy human colon tissues, cortactin co-localized with ZO-1 at epithelial cell contacts. In IBDs patients, we observed decreased cortactin levels and loss of co-localization with ZO-1. Thus, cortactin is a master regulator of intestinal epithelial barrier integrity in vivo and could serve as a suitable target for pharmacological intervention in IBDs.

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14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

Cited by 52 publications

References 69 publications

CUE domain‐containing protein 2 promotes the Warburg effect and tumorigenesis

CUE domain‐containing protein 2 promotes the Warburg effect and tumorigenesis

SRARP and HSPB7 are epigenetically regulated gene pairs that function as tumor suppressors and predict clinical outcome in malignancies

Cortactin deficiency causes increased RhoA/ROCK1-dependent actomyosin contractility, intestinal epithelial barrier dysfunction, and disproportionately severe DSS-induced colitis

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