SciCombinator

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Journal: Biochimica et biophysica acta. Molecular cell research

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Receptor Tyrosine Kinases are critical regulators of signal transduction that support cell survival, proliferation, and differentiation. . Dysregulation of normal Receptor Tyrosine Kinase function by mutation or other activity-altering event can be oncogenic or can impact the transformed malignant cell so it becomes particularly resistant to stress challenge, have increased proliferation, become evasive to immune surveillance, and may be more prone to metastasis of the tumor to other organ sites. The TAM family of Receptor Tyrosine Kinases (TYRO3, AXL, MERTK) are emerging as important components of malignant cell survival in many cancers. The TAM kinases are important regulators of cellular homeostasis and proper cell differentiation in normal cells as receptors for their ligands GAS6 and Protein S. They also are critical to immune and inflammatory processes. In malignant cells, the TAM kinases can act as ligand independent co-receptors to mutant Receptor Tyrosine Kinases and in some cases (e.g. FLT3-ITD mutant) are required for their function. They also have a role in immune checkpoint surveillance. At the time of this review, the Covid-19 pandemic poses a global threat to world health. TAM kinases play an important role in host response to many viruses and it is suggested the TAM kinases may be important in aspects of Covid-19 biology. This review will cover the TAM kinases and their role in these processes.

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A suite of adaptations allows insects to survive in hostile terrestrial environments for long periods of time. Temperature represents a key environmental factor for most ectothermic insects, and they rapidly acclimate to high and low temperatures. Vast amounts of data in this research field support the idea that an insect’s ability to tolerate fluctuating temperatures can be regarded as a biphasic hormetic dose response. Observation indicates that their thermal hormetic response represents a conservative estimate of their intrinsic capacity for rapid adaptation to environmental changes in nature because they naturally experience diel or seasonal temperature fluctuations. It is therefore reasonable to suppose that the hormetic response in insects reflects a surplus physiological capacity to deal with temperature changes that they would experience naturally. Although it has been unknown how thermal acclimation is induced, a stress-dependent increase in N-acetyltyrosine (NAT) was recently found to occur in insect larvae who had endured high temperatures. NAT treatment was demonstrated to induce thermotolerance in several tested insect species. NAT was also identified in the serum of humans as well as mice, and its concentration in mice was shown to be increased by heat and restraint stress, with NAT pretreatment lowering the concentrations of corticosterone and peroxidized lipids in stressed mice. These recent findings may give us some hints about how long a hormetic response lasts. Here, I will discuss recent findings underlying hormetic responses induced by an intrinsic factor, NAT, and how the hormetic response may begin and end.

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Biomolecular condensation through phase separation may be a novel mechanism to regulate bacterial processes, including cell division. Previous work revealed that FtsZ, a protein essential for cytokinesis in most bacteria, forms biomolecular condensates with SlmA, a protein that protects the chromosome from damage inflicted by the division machinery in Escherichia coli. The absence of condensates composed solely of FtsZ under the conditions used in that study suggested this mechanism was restricted to nucleoid occlusion by SlmA or to bacteria containing this protein. Here we report that FtsZ alone, under physiologically relevant conditions, can demix into condensates in bulk and when encapsulated in synthetic cell-like systems generated by microfluidics. Condensate assembly depends on FtsZ being in the GDP-bound state and on conditions mimicking the crowded environment of the cytoplasm that promote its oligomerization. Condensates are dynamic and reversibly convert into filaments upon GTP addition. Notably, FtsZ lacking its C-terminal disordered region, a structural element likely to favor biomolecular condensation, also forms condensates, albeit less efficiently. The inherent tendency of FtsZ to form condensates susceptible to modulation by physiological factors, including binding partners, suggests that such mechanisms may play a more general role in bacterial division than initially envisioned.

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Biomechanical properties of the cell nucleus play critical roles in cell behaviors and functions. As one important biomechanical property, the stiffness (or Young’s modulus) of the cell nucleus has been widely investigated by different techniques including atomic force microscopy (AFM). In most of previous studies, the stiffness of the nuclear region of an intact cell or the stiffness of the isolated nucleus was detected. In this study, we developed a strategy for in situ detecting the stiffness of the cell nucleus via AFM. The extranuclear components of adherent cells (endothelial cells) were in situ removed by Triton X-100 treatment and the bare, adherent nuclei were exposed for in situ AFM force measurement. We found that the nuclear regions of intact cells (5.59 ± 1.55 kPa) had a relatively higher average Young’s modulus than the nonnuclear regions (1.47 ± 0.77 kPa) and that the in situ exposed nuclei (22.06 ± 7.29 kPa) were much stiffer than the nuclear regions of intact cells. This strategy is very simple and effective for detecting the stiffness of the cell nucleus and potentially is promising for a wide application.

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The removal of cells by apoptosis is an essential process regulating tissue homeostasis. Cancer cells acquire the ability to circumvent apoptosis and survive in an unphysiological tissue context. Thereby, the Bcl-2 protein family plays a key role in the initiation of apoptosis, and overexpression of the anti-apoptotic Bcl-2 proteins is one of the molecular mechanisms protecting cancer cells from apoptosis. Recently, small molecules targeting the anti-apoptotic Bcl-2 family proteins have been identified, and with venetoclax the first of these BH3 mimetics has been approved for the treatment of leukemia. In solid tumors the anti-apoptotic Bcl-2 family proteins Mcl-1 and Bcl-xL are frequently overexpressed or genetically amplified. In this review, we summarize the role of Mcl-1 and Bcl-xL in solid tumors and compare the different BH3 mimetics targeting Mcl-1 or Bcl-xL.

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Calpain, a Ca2+-dependent cysteine protease, plays a significant role in gene expression, signal transduction, and apoptosis. Mutations in human calpain-5 cause autosomal dominant neovascular inflammatory vitreoretinopathy and the inhibition of calpain-5 activity may constitute an effective therapeutic strategy for this condition. Although calpain-5 is ubiquitously expressed in mammalian tissues and was recently found to be present in the mitochondria as well as in the cytosol, its physiological function and enzymological properties require further elucidation. The objective of the current study was to determine the characteristics of mitochondrial calpain-5 in porcine retinas, human HeLa cells, and C57BL/6J mice using subcellular fractionation. We found that mitochondrial calpain-5 was proteolyzed/autolyzed at low Ca2+ concentrations in mitochondria isolated from porcine retinas and by thapsigargin-induced endoplasmic reticulum (ER) stress in HeLa cells. Further, mitochondrial calpain-5, as opposed to cytosolic calpain-5, was activated during the early stages of ER stress in C57BL/6J mice. These results showed that mitochondrial calpain-5 was activated at low Ca2+ concentrations in vitro and in response to ER stress in vivo. The present study provides new insights into a novel calpain system in the mitochondria that includes stress responses during the early phases of ER stress. Further, activation of mitochondrial calpain-5 by treatment using low-molecular-weight compounds may have therapeutic potential for diseases related to ER stress, including neurodegenerative diseases, metabolic syndromes, diabetes, and cancer.

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T cell activation starts with formation of second messengers that release Ca2+ from the endoplasmic reticulum (ER) and thereby activate store-operated Ca2+ entry (SOCE), one of the essential signals for T cell activation. Recently, the steroidal 2-methoxyestradiol was shown to inhibit nuclear translocation of the nuclear factor of activated T cells (NFAT). We therefore investigated 2-methoxyestradiol for inhibition of Ca2+ entry in T cells, screened a library of 2-methoxyestradiol analogues, and characterized the derivative 2-Ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene (STX564) as a novel, potent and specific SOCE inhibitor. STX564 inhibits Ca2+ entry via SOCE without affecting other ion channels and pumps involved in Ca2+ signaling in T cells. Downstream effects such as cytokine expression and cell proliferation were also inhibited by both 2-methoxyestradiol and STX564, which has potential as a new chemical biology tool.

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Iron is an essential element for life. Cells develop mechanisms to tightly regulate its homeostasis, in order to avoid abnormal accumulation and the consequent cell toxicity. In budding yeast, the high affinity iron regulon is under the control of the transcription factor Aft1. We present evidence demonstrating that the MAPK Slt2 of the cell wall integrity pathway (CWI), phosphorylates and negatively regulates Aft1 activity upon the iron depletion signal, both in fermentative or respiratory conditions. The lack of Slt2 provokes Aft1 dysfunction leading to a shorter chronological life span. The signal of iron scarcity is not transmitted to Slt2 through other signalling pathways such as TOR1, PKA, SNF1 or TOR2/YPK1. The observation that Slt2 physically binds Aft1 rather suggests a direct regulation.

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Protein aggregation is a hallmark of neurodegenerative diseases. However, the mechanism that induces pathogenic aggregation is not well understood. Recently, it has emerged that several of the pathological proteins found in an aggregated or mislocalized state in neurodegenerative diseases are also able to undergo liquid-liquid phase separation under physiological conditions. Although these phase transitions are important for various physiological functions, neurodegenerative disease-related mutations and conditions can alter the LLPS behavior of these proteins, which can elicit toxicity. Therefore, therapeutics that antagonize aberrant LLPS may be able to mitigate toxicity and aggregation that is ubiquitous in neurodegenerative disease. Here, we discuss the mechanisms by which aberrant protein phase transitions may contribute to neurodegenerative disease. We also outline potential therapeutic strategies to counter deleterious phases.

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The Bcl-2-family proteins have long been known for their role as key regulators of apoptosis. Evidence has shown that overexpression of various members of the family is associated with oncogenesis and cancer therapy resistance. Its founding member, anti-apoptotic Bcl-2 regulates cell death at different levels, whereby Bcl-2 emerged as a major drug target to eradicate cancers through cell death. This resulted in the development of venetoclax, a Bcl-2 antagonist that acts as a BH3 mimetic. Venetoclax already entered the clinic to treat relapse chronic lymphocytic leukemia patients. Here, we discuss the role of Bcl-2 as a decision-maker in cell death with focus on the recent advances in anti-cancer therapeutics that target the BH4 domain of Bcl-2, thereby interfering with non-canonical functions of Bcl-2 in Ca2+-signaling modulation. In particular, we critically discuss previously developed tools, including the peptide BIRD-2 (Bcl-2/ IP3R-disrupter-2) and the small molecule BDA-366. In addition, we present a preliminary analysis of two recently identified molecules that emerged from a molecular modelling approach to target Bcl-2’s BH4 domain, which however failed to induce cell death in two Bcl-2-dependent diffuse large B-cell lymphoma cell models. Overall, antagonizing the non-canonical functions of Bcl-2 by interfering with its BH4-domain biology holds promise to elicit cell death in cancer, though improved tools and on-target antagonizing small molecules remain necessary and to be designed.