PHLD Class Proteins: A Family of New Players in the p53 Network

The Pleckstrin Homology-like Domain (PHLD) class of proteins are multifunctional proteins. The class is comprised of two families of proteins, PHLDA and PHLDB, each with 3 members. All members of the families possess a pleckstrin homology (PH) domain. Though identified nearly 30 years ago, this class of proteins remains understudied with PHLDA family members receiving most of the research attention. Recent studies have also begun to reveal the functions of the PHLDB family proteins in regulation of p53 and AKT signaling pathways important for cancer and metabolism. This review will discuss current research and offer some prospects on the possible roles of both families in cancer and metabolism.

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Regulated Membrane Localization of Tiam1, Mediated by the NH2-terminal Pleckstrin Homology Domain, Is Required for Rac-dependent Membrane Ruffling and C-Jun NH2-terminal Kinase Activation

The Journal of Cell Biology ◽

10.1083/jcb.137.2.387 ◽

1997 ◽

Vol 137 (2) ◽

pp. 387-398 ◽

Cited By ~ 165

Author(s):

Frits Michiels ◽

Jord C. Stam ◽

Peter L. Hordijk ◽

Rob A. van der Kammen ◽

Lisette Ruuls-Van Stalle ◽

...

Keyword(s):

Signaling Pathways ◽

Laser Scanning Microscopy ◽

Confocal Laser ◽

Membrane Localization ◽

Serum Starvation ◽

Pleckstrin Homology Domain ◽

Membrane Association ◽

Ph Domain ◽

Pleckstrin Homology ◽

Membrane Ruffling

Rho-like GTPases, including Cdc42, Rac, and Rho, regulate signaling pathways that control actin cytoskeletal structures and transcriptional activation. The Tiam1 gene encodes an activator of Rac1, and similarly to constitutively activated (V12)Rac1, overexpression of Tiam1 in fibroblasts induces the formation of membrane ruffles. Tiam1 contains a Dbl homology (DH) domain and adjacent pleckstrin homology (PH) domain, hallmarks for activators of Rho-like GTPases. Unique for Tiam1 are an additional PH domain and a Discs-large homology region in the NH2-terminal part of the protein. Here we show that both in fibroblasts and COS cells, membrane localization of Tiam1 is required for the induction of membrane ruffling. A detailed mutational analysis, in combination with confocal laser scanning microscopy and immunoelectron microscopy, demonstrates that the NH2-terminal PH domain of Tiam1, but not the DH-adjacent PH domain, is essential for membrane association. This NH2-terminal PH domain of Tiam1 can be functionally replaced by the myristoylated membrane localization domain of c-Src, indicating that the primary function of this PH domain is to localize the protein at the membrane. After serum starvation, both membrane association of Tiam1 and ruffling can be induced by serum, suggesting that receptor stimulation induces membrane translocation of Tiam1. Similar to V12Rac1, Tiam1 stimulates the activity of the c-Jun NH2-terminal kinase (JNK). This Rac-dependent stimulation of JNK also requires membrane association of Tiam1. We conclude that the regulated membrane localization of Tiam1 through its NH2-terminal PH domain determines the activation of distinct Rac-mediated signaling pathways.

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

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201005143818 ◽

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.

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Shame and blame: Secondary stigma among families of convicted sex offenders

Criminology & Criminal Justice ◽

10.1177/17488958211017391 ◽

2021 ◽

pp. 174889582110173

Author(s):

Douglas Evans ◽

Adam Trahan ◽

Kaleigh Laird

Keyword(s):

United States ◽

Criminal Justice ◽

Sex Offenders ◽

Justice System ◽

Sex Offender ◽

Family Members ◽

The United States ◽

Formerly Incarcerated ◽

Research Attention ◽

Sex Offender Registry

The detriment of incarceration experienced by the formerly incarcerated has been increasingly explored in the literature on reentry. A tangential but equally concerning issue that has recently received more research attention is the effect on family members of the incarcerated. The stigma of a criminal conviction is most apparent among families of convicted sex offenders, who experience consequences parallel to those of their convicted relative. Drawing from interviews with 30 individuals with a family member incarcerated for a sex offence in the United States, this study explores manifestations of stigma due to familial association. The findings suggest that families face negative treatment from social networks and criminal justice officials, engage in self-blame and that the media’s control over the narrative exacerbates family members’ experiences. Given the pervasiveness of criminal justice system contact, the rapid growth of the sex offender registry in the United States, and the millions of family members peripherally affected by one or both, justice system reforms are needed to ensure that family members are shielded from the harms of incarceration and registration.

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Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02167-2 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Sophia K. Theodossiou ◽

Jett B. Murray ◽

LeeAnn A. Hold ◽

Jeff M. Courtright ◽

Anne M. Carper ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Signaling Pathways ◽

Transforming Growth Factor ◽

Akt Signaling ◽

Cell Alignment ◽

Limited Information ◽

Akt Inhibitor ◽

Tenogenic Differentiation

Abstract Background Tissue engineered and regenerative approaches for treating tendon injuries are challenged by the limited information on the cellular signaling pathways driving tenogenic differentiation of stem cells. Members of the transforming growth factor (TGF) β family, particularly TGFβ2, play a role in tenogenesis, which may proceed via Smad-mediated signaling. However, recent evidence suggests some aspects of tenogenesis may be independent of Smad signaling, and other pathways potentially involved in tenogenesis are understudied. Here, we examined the role of Akt/mTORC1/P70S6K signaling in early TGFβ2-induced tenogenesis of mesenchymal stem cells (MSCs) and evaluated TGFβ2-induced tenogenic differentiation when Smad3 is inhibited. Methods Mouse MSCs were treated with TGFβ2 to induce tenogenesis, and Akt or Smad3 signaling was chemically inhibited using the Akt inhibitor, MK-2206, or the Smad3 inhibitor, SIS3. Effects of TGFβ2 alone and in combination with these inhibitors on the activation of Akt signaling and its downstream targets mTOR and P70S6K were quantified using western blot analysis, and cell morphology was assessed using confocal microscopy. Levels of the tendon marker protein, tenomodulin, were also assessed. Results TGFβ2 alone activated Akt signaling during early tenogenic induction. Chemically inhibiting Akt prevented increases in tenomodulin and attenuated tenogenic morphology of the MSCs in response to TGFβ2. Chemically inhibiting Smad3 did not prevent tenogenesis, but appeared to accelerate it. MSCs treated with both TGFβ2 and SIS3 produced significantly higher levels of tenomodulin at 7 days and morphology appeared tenogenic, with localized cell alignment and elongation. Finally, inhibiting Smad3 did not appear to impact Akt signaling, suggesting that Akt may allow TGFβ2-induced tenogenesis to proceed during disruption of Smad3 signaling. Conclusions These findings show that Akt signaling plays a role in TGFβ2-induced tenogenesis and that tenogenesis of MSCs can be initiated by TGFβ2 during disruption of Smad3 signaling. These findings provide new insights into the signaling pathways that regulate tenogenic induction in stem cells.

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Retraction Note: Chemopreventive Potential of Resveratrol in Mouse Skin Tumors Through Regulation of Mitochondrial and PI3K/AKT Signaling Pathways

Pharmaceutical Research ◽

10.1007/s11095-020-02973-y ◽

2021 ◽

Vol 38 (2) ◽

pp. 375-375

Author(s):

Preeti Roy ◽

Neetu Kalra ◽

Sahdeo Prasad ◽

Jasmine George ◽

Yogeshwer Shukla

Keyword(s):

Signaling Pathways ◽

Mouse Skin ◽

Akt Signaling ◽

Skin Tumors

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Brown alga Ecklonia cava attenuates type 1 diabetes by activating AMPK and Akt signaling pathways

Food and Chemical Toxicology ◽

10.1016/j.fct.2009.11.004 ◽

2010 ◽

Vol 48 (2) ◽

pp. 509-516 ◽

Cited By ~ 72

Author(s):

Changkeun Kang ◽

Yeung Bae Jin ◽

Hyunkyoung Lee ◽

Mijin Cha ◽

Eun-tae Sohn ◽

...

Keyword(s):

Type 1 Diabetes ◽

Signaling Pathways ◽

Brown Alga ◽

Akt Signaling ◽

Ecklonia Cava

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Veratrilla baillonii Franch exerts anti-diabetic activity and improves liver injury through IRS/PI3K/AKT signaling pathways in type 2 diabetic db/db mice

Journal of Functional Foods ◽

10.1016/j.jff.2020.104204 ◽

2020 ◽

Vol 75 ◽

pp. 104204

Author(s):

Cai-Jing He ◽

Li-Qun Ma ◽

Muhammad Sarfaraz Iqbal ◽

Xian-Ju Huang ◽

Jun Li ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathways ◽

Akt Signaling ◽

Type 2 Diabetic

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Pleckstrin homology domains: not just for phosphoinositides

Biochemical Society Transactions ◽

10.1042/bst0320707 ◽

2004 ◽

Vol 32 (5) ◽

pp. 707-711 ◽

Cited By ~ 151

Author(s):

M.A. Lemmon

Keyword(s):

Subcellular Localization ◽

Human Genome ◽

Small Gtpases ◽

Membrane Targeting ◽

Ph Domain ◽

Cellular Membranes ◽

Pleckstrin Homology ◽

Ph Domains ◽

Common Domain ◽

Homology Domains

PH domains (pleckstrin homology domains) are the 11th most common domain in the human genome and are best known for their ability to target cellular membranes by binding specifically to phosphoinositides. Recent studies in yeast have shown that, in fact, this is a property of only a small fraction of the known PH domains. Most PH domains are not capable of independent membrane targeting, and those capable of doing so (approx. 33%) appear, most often, to require both phosphoinositide and non-phosphoinositide determinants for their subcellular localization. Several recent studies have suggested that small GTPases such as ARF family proteins play a role in defining PH domain localization. Some others have described a signalling role for PH domains in regulating small GTPases, although phosphoinositides may also play a role. These findings herald a change in our perspective of PH domain function, which will be significantly more diverse than previously supposed.

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