AKT/PKB signaling: navigating downstream

ArticleinCell 129(7):1261-74 · July 2007with62 Reads
DOI: 10.1016/j.cell.2007.06.009 · Source: PubMed
Abstract
The serine/threonine kinase Akt, also known as protein kinase B (PKB), is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer. Here, we review the molecular properties of Akt and the approaches used to characterize its true cellular targets. In addition, we discuss those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration.
    • "The net protein loss in gastrocnemius muscle is likely due to a decreased Akt activation and an increased AMPK activation. Akt is phosphorylated and activated in a pathway triggered by insulin, which controls processes such as cell growth, metabolism, proliferation , glucose uptake, survival and angiogenesis [39]. Reduced circulating insulin means a reduction in Akt activation, leading to inhibition of mTORC1; whereas the phosphorylation by Akt, mTORC1 is activated, leading to protein synthesis process [40]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Cancer-cachexia state frequently induces both fat and protein wasting, leading to death. In this way, the knowledge of the mechanism of drugs and their side effects can be a new feature to treat and to have success, contributing to a better life quality for these patients. Metformin is an oral drug used in type 2 diabetes mellitus, showing inhibitory effect on proliferation in some neoplastic cells. For this reason, we evaluated its modulatory effect on Walker-256 tumour evolution and also on protein metabolism in gastrocnemius muscle and body composition. Methods: Wistar rats received or not tumour implant and metformin treatment and were distributed into four groups, as followed: control (C), Walker 256 tumour-bearing (W), metformin-treated (M) and tumour-bearing treated with metformin (WM). Animals were weighed three times a week, and after cachexia state has been detected, the rats were euthanised and muscle and tumour excised and analysed by biochemical and molecular assays. Results: Tumour growth promoted some deleterious effects on chemical body composition, increasing water and decreasing fat percentage, and reducing lean body mass. In muscle tissue, tumour led to a decreased protein synthesis and an increased proteolysis, showing the higher activity of the ubiquitin-proteasome pathway. On the other hand, the metformin treatment likely minimised the tumour-induced wasting state; in this way, this treatment ameliorated chemical body composition, reduced the higher activities of proteolytic enzymes and decreased the protein waste. Conclusion: Metformin treatment not only decreases the tumour growth but also improves the protein metabolism in gastrocnemius muscle in tumour-bearing rats.
    Full-text · Article · Dec 2016
    • "The phosphatidylinositol 3-kinases (PI3Ks) are a large family of lipid kinases, and play an important role in many cellular processes, such as cell survival, proliferation , and migration [1, 2]. PIK3CA, encoding for the catalytic subunit p110-alpha of class I PI3Ks, is a member of this lipid kinase family. "
    [Show abstract] [Hide abstract] ABSTRACT: Background The PIK3CAH1047R mutation is considered to be a potential predictive biomarker for EGFR-targeted therapies. In this study, we developed a novel PCR-PFLP approach to detect the PIK3CAH1047R mutation in high effectiveness. Methods A 126-bp fragment of PIK3CA exon-20 was amplified by PCR, digested with FspI restriction endonuclease and separated by 3 % agarose gel electrophoresis for the PCR-RFLP analysis. The mutant sequence of the PIK3CAH1047R was spiked into the corresponding wild-type sequence in decreasing ratios for sensitivity analysis. Eight-six cases of formalin-fixed paraffin-embedded colorectal cancer (CRC) specimens were subjected to PCR-RFLP to evaluate the applicability of the method. Results The PCR-RFLP method had a capability to detect as litter as 0.4 % of mutation, and revealed 16.3 % of the PIK3CAH1047R mutation in 86 CRC tissues, which was significantly higher than that discovered by DNA sequencing (9.3 %). A positive association between the PIK3CAH1047R mutation and the patients’ age was first found, except for the negative relationship with the degree of tumor differentiation. In addition, the highly sensitive detection of a combinatorial mutation of PIK3CA, KRAS and BRAF was achieved using individual PCR-RFLP methods. Conclusions We developed a sensitive, simple and rapid approach to detect the low-abundance PIK3CAH1047R mutation in real CRC specimens, providing an effective tool for guiding cancer targeted therapy.
    Full-text · Article · Dec 2016
    • "PIK3CA mutations and subsequent activation of the PI3K/AKT pathway play an essential role in cancer cell signaling pathways, involving growth factors, cytokines, and other cellular stimuli associated with human HR hasard ratio, CS cancer specific survival, RS recurrence-free survival rate, OS overall survival rate neoplasms [11, 12, 19, 20]. This study examined the prognostic impact of PIK3CA mutations on survival in patients with gastric cancer. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations that activate the PI3K/AKT signaling pathway have been observed in several types of carcinoma and have been associated with patient prognosis. However, the significance of PIK3CA mutations in gastric cancer remains unclear. This retrospective study investigated the relationship between PIK3CA mutations and clinical outcomes in patients with gastric cancer. Additionally, we reviewed the rate of PIK3CA mutations in gastric cancer and the association between PIK3CA mutations and prognosis in human cancers. Methods: The study included 208 patients with gastric cancer who underwent surgical resection at Kumamoto University Hospital, Japan, between January 2001 and August 2010. Mutations in PIK3CA exons 9 and 20 were quantified by pyrosequencing assays. Results: PIK3CA mutations were detected in 25 (12 %) of the 208 patients. Ten patients had c.1634A > G (p.E545G), 10 had c.1624G > A (p.E542K), 13 had c.1633G > A (p.E545K), nine had c.3139C > T (p.H1047R), and 1 had c.3140A > G (p.H1047Y) mutations. PIK3CA mutations were not significantly associated with any clinical, epidemiologic, or pathologic characteristic. Kaplan-Meier analysis showed no significant differences in disease-free survival (log rank P = 0.84) and overall survival (log rank P = 0.74) between patients with and without PIK3CA mutations. Conclusions: Mutations in PIK3CA did not correlate with prognosis in patients with gastric cancer, providing additional evidence for the lack of relationship between the two.
    Full-text · Article · Dec 2016
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