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MAPK signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Archana Devi, Bhavana Kushwaha, Gopal Gupta
The p38 mitogen-activated protein (MAP) kinases are serine-/threonine-based kinases composed of four members (p38α, p38β, p38γ and p38δ). These members show similarity in amino acid sequences, but their expression patterns are different (38). MAPK-p38 plays a key role in driving cellular activities in response to various extracellular stress stimuli. Interestingly, p38 MAPKs can also exert their function independent of its kinase activity, which it carries out by direct binding to its targets (39). Extracellular stress stimuli and inflammatory cytokines can also activate p38, which affects many biological activities downstream in the cell, such as inflammation, apoptosis, cell differentiation and the cell cycle (40). The upstream kinases MKK3 and MKK6 are responsible for p38 MAPK activation (41). Its activity is mainly controlled by phosphorylation-dephosphorylation mechanisms, and the duration of phosphorylation is pivotal in regulating cell fate (42). The MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2), the well-known substrate of MAPK p38, has been demonstrated to activate various transcription factors such as ATF1, c-Fos and c-Jun, which are reported to regulate steroid biosynthesis (43), and the molecular chaperone heat shock protein 27(Hsp27) that regulates actin dynamics to prevent its destabilization during stress (44). Besides MK2, Na+/H+ exchangers (NHE) are also reported as a substrate for p38MAPK, which ensures the spermatogenic event and the spermatozoal maturation by regulating pH and ionic balance (45,46).
Tuberous Sclerosis Complex
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Joana Jesus Ribeiro, Filipe Palavra, Flávio Reis
Substantial progress has been made in the past years toward understanding the normal cellular functions of the TSC1–TSC2 protein complex [11,27,43]. One of the first mechanistic clues to the roles that TSC1 and TSC2 proteins have in cell function was the finding that mutations in the drosophila Tsc1 and Tsc2 homologs increased cell and organ size [44]. Subsequent experiments demonstrated that hamartin and tuberin form an intracellular heterodimeric complex with GTPase-activating protein activity that inhibits Rheb, responsible for the activation of the mTOR [27,42]. After growth-factor stimulation, the hamartin–tuberin complex is phosphorylated and its GTPase-activating protein activity is decreased [1]. Multiple kinases phosphorylate and inactivate TSC2 and thereby activate Rheb and mTOR: protein kinase B (AKT), mitogen-activated protein kinase–activated protein kinase 2 (MK2), p90 ribosomal S6 kinase 1 (RSK1) and extracellular-related kinase 2 (ERK2) [28,45–47]. By contrast, in response to stimuli such as hypoxia or energy deprivation, TSC1 and TSC2 proteins are phosphorylated, their GTPase-activating protein activity increases, and the complex deactivates Rheb by causing GTP to be cleaved from it. TSC2 is phosphorylated and activated by AMP-activated protein kinase (AMPK), and the phosphorylation of TSC1 by glycogen synthase kinase 3β (GSK3β) increases the stability of the TSC1–TSC2 complex [28,48,49]. Additional proteins known to interact with either TSC1 or TSC2 are rabaptin-5, 14-3-3, estrogen receptor α, calmodulin, p27, SMAD2 and SMAD3 (the human isoform homologs of Drosophila mothers against decapentaplegic), protein associated with Myc (PAM) and cyclin-dependent kinase 1 (CDK1) [43,50–54]. TSC1 and TSC2 proteins have additional roles besides the modulation of mTOR, since inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin [28,55].
Inhibition of MK2 kinase as a potential therapeutic target to control neuroinflammation in Alzheimer’s disease
Published in Expert Opinion on Therapeutic Targets, 2021
Shriyansh Srivastava, Rohan Rajopadhye, Mangaldeep Dey, Rakesh Kumar Singh
Several models of AD display sustained and chronic inflammatory biomarkers in brain tissues along with the pathological hallmarks. These biomarkers modulate the pathological hallmarks of AD leading to progressive neurodegeneration and are linked directly to memory impairment, cognitive deficits, and dementia. Thus, chronic neuroinflammation has emerged as a third important core pathological feature of AD. The microglia, astrocytes, and other neuronal cells are normally involved in neuroprotective functions by generating anti-Aβ antibodies and promoting CNS to peripheral clearance of excess Aβ in the brain [5,6]. However, during the excess cerebral load of Aβ deposits and soluble Aβ42 in the brain, the toll-like receptors (TLR4) present on the surface of these neuronal cells get activated. This further modulates p38MAPK (p38 mitogen-activated protein kinase) pathway resulting into a downstream activation of MK2 (MAPKAPK2, MAPK-activated protein kinase 2) in CNS. The activation of MK2 primarily regulates the transcriptional activation of pro-inflammatory cytokines, chemokines, and neurotoxic substances in the brain. The mediators are involved in amplifying the inflammatory responses and, in turn, lead to microglial auto-activation [7,8]. Thus, MK2 is thought to play a central role in regulation of chronic neuronal neuroinflammation in the brains and, therefore, can be a novel and attractive therapeutic target in AD.
Clinical relevance of understanding mitogen-activated protein kinases involved in asthma
Published in Expert Review of Respiratory Medicine, 2020
Corrado Pelaia, Alessandro Vatrella, Claudia Crimi, Luca Gallelli, Rosa Terracciano, Girolamo Pelaia
Among the four known isoforms of p38 MAPK, named α, β, γ, and δ, p38α appears to be the most important for the development of airway inflammation in asthma [8]. Indeed, p38 MAPK induces the production of many pro-inflammatory cytokines, and also promotes the chemotaxis and recruitment of inflammatory cells [18,19]. By analogy with the other MAPK subfamilies, also p38 activation is mediated by a phosphorylation cascade (Figure 1) triggered by specific MAPKKKs including apoptosis signal-regulating kinases 1/2 (ASK1/2) and TGF-β-activated kinase 1 (TAK/1), that phosphorylate MAPKKs MKK3/6 and MKK4, which in turn catalyze the phosphorylation-dependent activation of p38 MAPK [5]. As a result of this sequential process, p38 becomes able to phosphorylate several different substrates, also including MAPKAPK2 (MK2). By phosphorylating two critical serine residues (Ser-52 and Ser-178), MK2 inactivates tristetraprolin, a regulatory protein which exerts relevant anti-inflammatory effects via destabilization of several mRNAs transcribed from genes encoding various pro-inflammatory cytokines [20]; as a consequence, p38 signaling pathway stabilizes these mRNAs and is thus responsible for an increased cytokine biosynthesis [21].
Precision medicine for TP53-mutated acute myeloid leukemia
Published in Expert Review of Precision Medicine and Drug Development, 2019
Marte Karen Brattås, Håkon Reikvam, Tor Henrik Anderson Tvedt, Øystein Bruserud
MAPKAP kinase 2 (mitogen-activated protein kinase-activated protein kinase 2) is also a G2/M regulator [54] that is a downstream target of p38, and inhibition of the p38/MAPKAP kinase 2 axis overcomes the resistance of primary AML cells to targeting of the intracellular inhibitors of apoptosis proteins (IAPs) [82]. Finally, polo-like kinase 1 is another G2/M checkpoint regulator, and inhibitors of this kinase seems to have antileukemic effects both in vitro and in clinical studies of AML [83].