PTEN Regulates Collagen-Induced Platelet Activation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5126-5126
Author(s):  
Zhen Weng ◽  
Ding Li ◽  
Lin Zhang ◽  
Changgeng Ruan ◽  
Guo-Qiang Chen ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Platelet Activation ◽  
Bleeding Time ◽  
Conflicts Of Interest ◽  
Akt Signaling ◽  
Pi3k Inhibitor ◽  
Akt Signaling Pathway ◽  
Mouse Blood ◽  
Induced Aggregation

Abstract Abstract 5126 PI3K has been shown to play an important role in collagen-induced platelet activation, but the role(s) of PTEN, a major regulator of the PI3K/Akt signaling pathway, has not been examined in platelets. Here, we report that PTEN−/− mouse blood contains 25% more platelets than PTEN+/+ blood, and that PTEN deficiency significantly shortened the bleeding time, increased the sensitivity of platelets to collagen-induced activation and aggregation, and enhanced phosphorylation of Akt at Ser473 in response to collagen. Furthermore, we found that PP2, and the combination of apyrase, indomethcin+1B5, respectively inhibited collagen-induced aggregation in both PTEN+/+ and PTEN−/− platelets. In contrast, LY294002 (a PI3K inhibitor) prevented the aggregation of PTEN+/+, but not PTEN−/− platelets. Therefore, PTEN apparently regulates collagen-induced platelet activation through PI3K/Akt dependent and independent signaling pathways. Disclosures: No relevant conflicts of interest to declare.

PTEN regulates collagen-induced platelet activation

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2579-2581 ◽  
Author(s):  
Zhen Weng ◽  
Ding Li ◽  
Lin Zhang ◽  
Jian Chen ◽  
Changgeng Ruan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Platelet Activation ◽  
Bleeding Time ◽  
Akt Signaling ◽  
Pi3k Inhibitor ◽  
Akt Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Mouse Blood ◽  
Induced Aggregation

Abstract Phosphatidylinositol 3-kinase (PI3K) has been shown to play an important role in collagen-induced platelet activation, but the role(s) of PTEN, a major regulator of the PI3K/Akt signaling pathway, has not been examined in platelets. Here, we report that Pten−/− mouse blood contains 25% more platelets than Pten+/+ blood and that PTEN deficiency significantly shortened the bleeding time, increased the sensitivity of platelets to collagen-induced activation and aggregation, and enhanced phosphorylation of Akt at Ser473 in response to collagen. Furthermore, we found that PP2, and the combination of apyrase, indomethacin + 1B5, respectively, inhibited collagen-induced aggregation in both PTEN+/+ and PTEN−/− platelets. In contrast, LY294002 (a PI3K inhibitor) prevented the aggregation of PTEN+/+, but not PTEN−/−, platelets. Therefore, PTEN apparently regulates collagen-induced platelet activation through PI3K/Akt-dependent and -independent signaling pathways.

scholarly journals Antiplatelet and Antithrombotic Effects of Isaridin E Isolated from the Marine-Derived Fungus via Downregulating the PI3K/Akt Signaling Pathway

Marine Drugs ◽  
2021 ◽  
Vol 20 (1) ◽  
pp. 23
Author(s):  
Ni Pan ◽  
Zi-Cheng Li ◽  
Zhi-Hong Li ◽  
Sen-Hua Chen ◽  
Ming-Hua Jiang ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Signaling Pathway ◽  
Platelet Activation ◽  
Bleeding Time ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Risk Of Bleeding ◽  
Antithrombotic Effects

Isaridin E, a cyclodepsipeptide isolated from the marine-derived fungus Amphichorda felina (syn. Beauveria felina) SYSU-MS7908, has been demonstrated to possess anti-inflammatory and insecticidal activities. Here, we first found that isaridin E concentration-dependently inhibited ADP-induced platelet aggregation, activation, and secretion in vitro, but did not affect collagen- or thrombin-induced platelet aggregation. Furthermore, isaridin E dose-dependently reduced thrombosis formation in an FeCl3-induced mouse carotid model without increasing the bleeding time. Mechanistically, isaridin E significantly decreased the ADP-mediated phosphorylation of PI3K and Akt. In conclusion, these results suggest that isaridin E exerts potent antithrombotic effects in vivo without increasing the risk of bleeding, which may be due to its important role in inhibiting ADP-induced platelet activation, secretion and aggregation via the PI3K/Akt pathways.

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

Akt-Mediated Phosphorylation of Bmi1 Regulates Its Chromatin Association and Growth Promoting Properties.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3605-3605
Author(s):  
Yan Liu ◽  
Fan Liu ◽  
Xinyang Zhao ◽  
Goro Sashida ◽  
Anthony Deblasio ◽  
...  
Keyword(s):  
Stem Cell ◽  
Signaling Pathway ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Akt Signaling ◽  
Polycomb Group ◽  
Akt Pathway ◽  
Akt Signaling Pathway ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 3605 Poster Board III-541 The Polycomb group (PcG) protein Bmi1 maintains silencing of the Ink4a-Arf locus and plays a key role in stem cell self-renewal and oncogenesis. The phosphoinositide 3-kinase-Akt (PI3K-Akt) signaling pathway regulates cell survival, growth, metabolism, migration and angiogenesis. In response to acute Pten loss (which results in Akt activation), mouse embryonic fibroblasts (mefs) accumulate p16Ink4a and p19Arf and undergo senescence. Similarly, Bmi1 −/− mefs undergo premature senescence and accumulate p16Ink4a and p19Arf. PTEN and Bmi1 have similar effects on hematopoiesis; Pten deletion promotes hematopoietic stem cell (HSC) proliferation, resulting in HSC depletion, whereas loss of Bmi1 impairs HSC self-renewal capability, also leading to bone marrow failure. These similarities led us to examine whether the PI3K/Akt pathway functions upstream of Bmi1 to negatively regulate its function and indeed we found that PKB/Akt phosphorylates Bmi1 in vivo, which results in its dissociation from chromatin and in de-repression of the Ink4a-Arf locus. Furthermore, activation of the PI3K/Akt pathway suppresses the ability of Bmi1 to promote cell growth and tumourigenesis and decreases the global level of histone H2A ubiquitination. PI3K/Akt signaling is not active in hematopoietic stem cells, but it is active in more committed progenitor cells. Thus, phosphorylation and inactivation of Bmi1 by Akt may limit HSC self-renewal. Our study also provides a mechanism for the upregulation of p16Ink4a and p19Arf seen in cancer cells that have activation of the PI3K/Akt signaling pathway, and identifies important crosstalk between phosphorylation and chromatin structure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Metformin alleviates the calcification of aortic valve interstitial cells through activating the PI3K/AKT pathway in an AMPK dependent way

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Qiao En ◽  
Huang Zeping ◽  
Wang Yuetang ◽  
Wang Xu ◽  
Wang Wei
Keyword(s):  
Aortic Valve ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Interstitial Cells ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Pathological Mechanism

Abstract Background Calcific aortic valve disease (CAVD) is the most prevalent valvular disease worldwide. However, no effective treatment could delay or prevent the progression of the disease due to the poor understanding of its pathological mechanism. Many studies showed that metformin exerted beneficial effects on multiple cardiovascular diseases by mediating multiple proteins such as AMPK, NF-κB, and AKT. This study aims to verify whether metformin can inhibit aortic calcification through the PI3K/AKT signaling pathway. Methods We first analyzed four microarray datasets to screen differentially expressed genes (DEGs) and signaling pathways related to CAVD. Then aortic valve samples were used to verify selected genes and pathways through immunohistochemistry (IHC) and western blot (WB) assays. Aortic valve interstitial cells (AVICs) were isolated from non-calcific aortic valves and then cultured with phosphate medium (PM) with or without metformin to verify whether metformin can inhibit the osteogenic differentiation and calcification of AVICs. Finally, we used inhibitors and siRNA targeting AMPK, NF-κB, and AKT to study the mechanism of metformin. Results We screened 227 DEGs; NF-κB and PI3K/AKT signaling pathways were implicated in the pathological mechanism of CAVD. IHC and WB experiments showed decreased AMPK and AKT and increased Bax in calcific aortic valves. PM treatment significantly reduced AMPK and PI3K/AKT signaling pathways, promoted Bax/Bcl2 ratio, and induced AVICs calcification. Metformin treatment ameliorated AVICs calcification and apoptosis by activating the PI3K/AKT signaling pathway. AMPK activation and NF-κB inhibition could inhibit AVICs calcification induced by PM treatment; however, AMPK and AKT inhibition reversed the protective effect of metformin. Conclusions This study, for the first time, demonstrates that metformin can inhibit AVICs in vitro calcification by activating the PI3K/AKT signaling pathway; this suggests that metformin may provide a potential target for the treatment of CAVD. And the PI3K/AKT signaling pathway emerges as an important regulatory axis in the pathological mechanism of CAVD.

scholarly journals The role of PI3K/Akt signaling pathway in non‐physiological shear stress‐induced platelet activation

2019 ◽  
Vol 43 (9) ◽  
pp. 897-908 ◽  
Author(s):  
Zengsheng Chen ◽  
Tieluo Li ◽  
Kafayat Kareem ◽  
Douglas Tran ◽  
Bartley P. Griffith ◽  
...  
Keyword(s):  
Shear Stress ◽  
Signaling Pathway ◽  
Platelet Activation ◽  
Akt Signaling ◽  
Akt Signaling Pathway

scholarly journals TLR2-PI3K/Akt Signaling Pathway Involved in Platelet Activation Induced By Group B Streptococci

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4635-4635
Author(s):  
Liping Ma ◽  
Xiaoyan Liu ◽  
Hongyun Liu ◽  
Shuangfeng Xie ◽  
Yanmin Gao ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Platelet Aggregation ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Platelet Activation ◽  
Surface Expression ◽  
Akt Signaling ◽  
Human Platelets ◽  
Akt Signaling Pathway ◽  
Group B Streptococci

Abstract Background Platelets not only play an important role in the initiation of hemostasis and thrombosis, but also participate in the immune and inflammatory response. Most studies focus on the platelets-bacteria interaction and demonstrate that bacteria are capable of binding to, aggregating and activating platelets. Human platelets are reported to express several groups of TLRs, which participate in the inflammation process and monitoring host infection. Recent data from our laboratory demonstrated that Group B streptococci (GBS) could induce platelet aggregation and up-regulate the expression of CD62P and further study showed that platelet TLR2 might involve in the activation. GBS, or streptococcus agalactiae, is one of the most common cause of life-threatening sepsis, pneumonia and meningitis in neonates, pregnant women, the elderly and immunocompromised adults. Therefore, illuminating the mechanisms of GBS-induced platelet activation is important for providing the basis for platelets in defense against infection and immunity. Since increasing reports have shown that the PI3-K/Akt signaling pathway regulates platelet activation and hemostasis, so it is possible to research the TLR2 related signaling pathway. Methods 1. Platelets were from healthy volunteers (all genders, 25-52 years old) who had not taken any anti-platelet drugs (like aspirins, clopidogrel and abciximab) during the previous 30 days. GBS 639 were isolated from patient's venous blood. 2. Platelet aggregation, the expression of platelet CD62P and PAC-1 were used as the indicator of platelet activation. GBS-induced platelet aggregation was assayed by light transmission; platelet TLR2, CD62P and PAC-1 expression were determined by flow cytometry; AKT and AKT phosphorylation expression were determined by RT-PCR or western blot assay. In some experiments, platelets were pre-incubated with PI3-K specific inhibitors LY294002 or anti-TLR2 monoclonal antibody. 3. Statistical analysis: Data are reported as the mean ± SD. Treatment groups were compared with the appropriate control (s), and statistical significance was examined using the two-tailed t-test. Differences were considered significant when P <0.05. All values were analyzed using SPSS version 17.0 software. Results 1. Platelet activation and TLR2 protein expression: Platelet aggregation, surface expression of TLR2, CD62P and PAC-1 induced by GBS were increased significantly on the platelets upon activation with GBS 639. However incubated with anti-TLR2 monoclonal antibody, they all decreased. 2. PI3-K/Akt signaling pathway: Real-time PCR showed that the PI3-K and Akt mRNA expression levels were increased significantly in the platelets stimulated with GBS 639. Western blot results showed that of Akt phosphorylation triggered by GBS was occurred as early as 15 min and increased gradually to reach a peak at 2 h post-infection and no significant changes were observed in total Akt protein expression during the infection. However, the expression of p-Akt, platelet aggregation and surface expression of CD62P and PAC-1 induced by GBS were significantly inhibited in the presence of a PI3-K inhibitor LY294002. 3. The relationship between TLR2 and PI3-K/Akt signaling pathway in platelet activation: Platelet p-Akt expression levels induced by GBS were significantly decreased after the activity of platelet TLR2 was blocked by anti-TLR2 monoclonal antibody, and no significant changes in total Akt protein expression. Conclusions GBS induced platelet activation through the TLR2-PI3-K/Akt signaling pathway in human platelets. Disclosures No relevant conflicts of interest to declare.

scholarly journals Integrin αIIbβ3-Mediated Outside-in Signaling: Brake or Amplifier of Platelet Activation?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4161-4161
Author(s):  
Baiyun Dai ◽  
Peng Wu ◽  
Feng Xue ◽  
Renchi Yang ◽  
Ziqiang Yu ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ligand Binding ◽  
Signaling Pathway ◽  
Platelet Activation ◽  
Low Dose ◽  
Akt Signaling ◽  
Negative Regulator ◽  
Akt Signaling Pathway ◽  
Integrin Αiibβ3 ◽  
Granule Secretion

Abstract αIIbβ3 is the most prominent integrin in platelets, and binding to its ligands, in addition to supporting platelet aggregation, also results in the transmission of so-called αIIbβ3-mediated outside-in signals into the cell interior. While it is well accepted that integrin-mediated outside-in signaling functions as an amplifier of platelet activation, accumulating evidence suggests that outside-in signaling can, under certain conditions, function as an inhibitor of platelet activation. In this regard, previous studies have shown that ligand binding and platelet aggregation activate the inositol phosphatase SHIP-1, a negative regulator of the PI3K/Akt signaling pathway, to shift activated integrins back to their resting state, leading to dissociation of platelet aggregates. Because the PI3K/Akt signaling pathway is also involved in platelet granule secretion, we examined whether ligand binding to αIIbβ3 might transmit inhibitory signals that suppress platelet granule secretion. Interestingly, we found that antagonists of integrin αIIbβ3 promote both platelet dense- and α-granule secretion stimulated by low dose agonists. In support of this finding, both mouse and human platelets lacking expression of αIIbβ3 exhibited increased granule secretion compared to their wild-type counterparts. Conversely, Mn++-induced fibrinogen binding to αIIbβ3 inhibited low-dose agonist-induced platelet granule secretion. Biochemical analysis revealed that blocking ligand binding to, or absence of, αIIbβ3, enhanced agonist-induced Akt phosphorylation, while at the same time prevented the activation of the inhibitory enzyme, SHIP-1. To further investigate the role of SHIP-1 in inhibitory signaling, we examined the effect on platelet secretion of 3AC, a specific inhibitor of SHIP-1. We found that 3AC not only restores ADP-induced platelet granule secretion, but also increases CRP- or TRAP-induced platelet granule secretion. Taken together, these data demonstrate that integrin αIIbβ3-mediated outside-in signaling act as a brake to restrict unnecessary platelet activation that occurs in the presence of low-dose agonist stimulation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Tuftelin 1 (TUFT1) Promotes the Proliferation and Migration of Renal Cell Carcinoma via PI3K/AKT Signaling Pathway

2021 ◽  
Vol 27 ◽  
Author(s):  
Hua Lin ◽  
Weifeng Zeng ◽  
Yuhang Lei ◽  
Desheng Chen ◽  
Zhen Nie
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Growth ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Renal Cell ◽  
Akt Signaling ◽  
Pi3k Inhibitor ◽  
Akt Signaling Pathway ◽  
And Migration ◽  
Proliferation And Migration

Tuftelin 1 (TUFT1), a protein functioning distinctively in different tissues, is reported to be elevated in several types of cancers and the elevation of TUFT1 is correlated with unfavorable clinicopathologic characteristics and poor survival. However, the involvement of TUFT1 in renal cell carcinoma (RCC) remains unknown. In the current study, we investigated the role of TUFT1 in RCC and potential underlying mechanisms. RT-PCR and Western blot analysis showed that both the mRNA and protein levels of TUFT1 were increased in primary RCC tissue and RCC cell lines. TUFT1 overexpression in RCC cells resulted in enhanced cell proliferation and migration while knockdown of TUFT1 by contrast decreased the growth and migration of the RCC cells, indicating TUFT1 expression is involved in RCC cell growth and migration. The involvement of TUFT1 in the epithelial-mesenchymal transition (EMT) of RCC cells was also determined by measuring the expression of EMT-related markers. Our data showed that TUFT1 overexpression promoted RCC cell EMT progression while knockdown of TUFT1 suppressed such process. Further signaling pathway inhibition assay revealed that TUFT1-induced RCC cell growth, migration and EMT was significantly suppressed by PI3K inhibitor, but not JNK or MEK inhibitors. In addition, TUFT1 overexpression enhanced the AKT phosphorylation, a key member of the PI3K signaling pathway, while PI3K inhibitor suppressed such process. Taken together, our study showed that TUFT1 expression was elevated in RCC and such elevation promoted the proliferation, migration and EMT of RCC cells in vitro, through PI3K/AKT signaling pathway. The findings of our current study imply that TUFT1 is involved in RCC tumorigenesis, and it may serve as a biomarker for RCC diagnosis and a potential target for RCC treatment.

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