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Tuberous Sclerosis Complex
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Joana Jesus Ribeiro, Filipe Palavra, Flávio Reis
mTOR is a serine/threonine protein kinase, member of the phosphoinositide 3-kinase-(PI3K)-related kinase family and of cell survival pathways [58,61]. mTOR functions in two separate pathways, with two distinct protein complexes: mTORC1 and mTORC2 [61–63]. Both mTOR complexes are large, with mTORC1 having six and mTORC2 seven known protein components [62]. The common proteins are the catalytic mTOR subunit; mammalian lethal with sec-13 protein 8 (mLST8, also known as GβL), which works as a positive regulator; DEP domain containing mTOR-interacting protein (DEPTOR), negative regulator and the tti1/tel2 complex [62,64]. mTORC1 is inhibited by the action of rapamycin and consists of regulatory-associated protein of mTOR (Raptor), a positive regulator involved in substrate recruitment; and proline-rich AKT substrate of 40 kDa (PRAS40), responsible for mTORC1 inhibition [56,61,63]. The second pathway, involving mTORC2, requires binding mTOR to rapamycin-insensitive companion of mTOR (Rictor), essential for the interaction between mTORC2 and TSC2; mammalian stress-activated protein kinase interacting protein (mSIN-1), important for complex construction; and the protein observed with rictor 1 and 2 (PROTOR 1/2), which seems to have a role in enabling mTORC2 to activate serum-and glucocorticoid−induced kinase 1 (SGK1) [58,61–63]. mTORC2 is rapamycin-insensitive and functions upstream of Rho GTPases to regulate the actin cytoskeleton [56,61,64]. TSC1-TSC2 complex negatively regulates mTORC1 [28,62].
The Endometrial Factor in Recurrent Pregnancy Loss
Published in Howard J.A. Carp, Recurrent Pregnancy Loss, 2020
Luiza Borges Manna, Ying Cheong
Multiple attempts have been made to identify biomarkers of adequate decidualization, although their clinical applicability is still controversial [9]. Prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP-1) have been historically used as markers of an appropriate decidua [5]. Salker et al. [10] have shown that PRL levels are approximately 100-fold lower in the endometrium of women suffering from RPL when compared to controls, indicating that this population might be unable to mount an adequate decidual response. In addition, expression of PROK1, a key regulator of endometrial receptivity, was significantly increased in patients affected by RPL and this continued to rise aberrantly throughout the cycle, pointing toward an impairment of temporal regulation of decidual changes. In a different study, similar disruption of decidual response was caused by untimely expression of serum- and glucocorticoid-inducible kinase 1 (SGK1). Whereas continuous expression of this kinase was associated with complete infertility, a blunted increase was found in RPL cases, likely due to persistently high reactive oxygen species that prevented the maintenance of pregnancy [11]. An abnormal decidual response to embryonic signals has also been demonstrated. Human chorionic gonadotrophin (hCG), secreted early by the trophoblast, is known to inhibit both PRL and IGFBP-1 in a dose- and time-dependent manner [12] in normal pregnancies. Whereas hCG was successful in reducing PRL and PROK1 in controls, the opposite occurred in RPL samples [10].
Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
There are distinct histological, genotypic and immunophenotypic features between the Hodgkin/Reed–Sternberg (HRS) cell in cHL, and the malignant cell in NLPHL, known as the lymphocyte predominant (LP) cell. The LP cell has a ‘popcorn’ appearance, strongly expresses B-cell markers, is usually negative for EBV and mutations of SGK1, DUSP2 and JUNB play an important role in the molecular pathogenesis. These genetic features are epitomize the clonal relatedness of NLPHL and DLBCL (Figures 10.4 and 10.5). Additionally, there are differences in the composition of the microenvironment’s inflammatory cells, with LP cells being surrounded by rosetting follicular helper T-cells (CD3, CD4, CD57 and PD-1 positive) and HRS cells with large number of reactive B- and T-cells (T-helper, T-regulatory and cytotoxic T-cells), histiocytes, plasma cells, eosinophils and neutrophils.
Serum- and glucocorticoid-induced kinase 1, a new therapeutic target for autophagy modulation in chronic diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Inés Maestro, Patricia Boya, Ana Martinez
SGK1 is a serine/threonine kinase belonging to the ACG kinase family. A large body of evidence gathered over the last two decades confirms that dysregulation or dysfunction of SGK1 is a feature of many pathologies, including cancer, diabetes, hypertension, cardiovascular and thrombotic diseases, and neurodegenerative diseases. Importantly, these are all severe, chronic human diseases for which the development of new pharmacological therapies is of the utmost importance. The discovery of new therapeutic targets and small molecules that can modulate their activity is crucial to provide patients with alternative treatment options that can improve their quality of life. A key risk factor for several of the aforementioned diseases is increasing age. The gradual and progressive increase in current life expectancy is yet another reason why the recent research focus on SGK1 as a therapeutic target is well warranted.
Identification of a new structural family of SGK1 inhibitors as potential neuroprotective agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Ines Maestro, Enrique Madruga, Patricia Boya, Ana Martínez
These data make SGK1 a potential pharmacological target for different pathological situations, especially in neurodegeneration, a field still to be explored. In fact, there are already some SGK1 inhibitors described in the literature. The most used are a pyrrolo-pyridine compound GSK650394 (IC50: 62 nM) developed by GlaxoSmithKline15, a phenylbenzohydrazide EMD638683 (IC50: 3 µM), developed by Merck16, and a pyrazolopyrimidine-based compound SI113 (IC50: 600 nM)17, (Figure 2). However, they have been mainly applied in cancer research and their ability to cross human blood brain barrier (BBB) is unknown. Due to the relevance role of SGK1 in neurodegeneration, its modulation in the CNS must be explored.