The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.

SUMMARY The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH>7.9. The alkali-sensing property of IRR is conserved in frog, mouse and human. IRR activation is specific, dose-dependent, quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess.

The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells.

The major protein of cytoplasmic mRNPs from rabbit reticulocytes, YB-1, is a member of an ancient family of proteins containing a common structural feature, coldshock domain. In eukaryotes, this family is represented by multifunctional mRNA/Y-box DNA-binding proteins that control gene expression at different stages. To address possible post-transcriptional regulation of YB-1 gene expression, we examined effects of exogenous 5-and 3-untranslatable region-containing fragments of YB-1 mRNA on its translation and stability in a cell-free system. The addition of the 3 mRNA fragment as well as its subfragment I shut off protein synthesis at the initiation stage without affecting mRNA stability. UV crosslinking revealed four proteins (69, 50, 46, and 44 kDa) that specifically interacted with the 3 mRNA fragment; the inhibitory subfragment I bound two of them, 69-and 50-kDa proteins. We have identified these proteins as PABP (poly(A)-binding protein) (69 kDa) and YB-1 (50 kDa) and demonstrated that titrating out of PABP by poly(A) strongly and specifically inhibits YB-1 mRNA cap ؉ poly(A) ؊ translation in a cell-free system. Thus, PABP is capable of positively affecting YB-1 mRNA translation in a poly(A) tail-independent manner.The evolutionarily conserved family of cold-shock domaincontaining proteins (CSD proteins) 1 is represented in organisms from bacteria to man by multifunctional DNA/RNA-binding proteins (1, 2). In bacteria, some of them known as major cold-shock proteins are responsible for adaptation to growth at low temperatures, and their expression is enormously activated with a temperature decrease (3, 4). In mammalian cells, CSD proteins regulate cell proliferation and differentiation and are involved in cell defense systems (5-11). In the cell nucleus, CSD proteins regulate transcription by interacting with promoters and enhancers of many genes (9, 12-17). They are also involved in DNA replication and repair, as well as in mRNA splicing (5, 18 -20). In the cytoplasm, CSD proteins bind mRNAs, affecting their translation fate (21-28) and extending their lifetime (29).In bacteria, accumulation of major cold-shock proteins at low temperatures was shown to result mainly from strong and selective stabilization of their mRNAs (30, 31). The crucial role of eukaryotic CSD proteins in major cellular events suggests that there is precise regulation of their expression. At present the post-transcriptional control of eukaryotic gene expression is to a large extent attributed to the presence of specific sequences within mRNA 5Ј-and 3Ј-untranslatable regions (UTRs), which serve as targets for binding of certain proteins and complementary RNAs (32, 33). Here, we studied this type of regulation during in vitro synthesis of rabbit p50, a member of the eukaryotic CSD protein family, which is the major protein of reticulocyte mRNPs and is virtually identical to the human Y-box binding protein YB-1. To determine a possible role of YB-1 mRNA UTRs in YB-1 post-transcriptional regulation, we examined effects of exogenous mRNA f...

Macromolecules gain access to the cytoplasm of eukaryotic cells using one of several ways of which clathrin-dependent endocytosis is the most researched. Although the mechanism of clathrin-mediated endocytosis is well understood in general, novel adaptor proteins that play various roles in ensuring specific regulation of the mentioned process are being discovered all the time. This review provides a detailed account of the mechanism of clathrin-mediated internalization of activated G protein-coupled receptors, as well as a description of the major proteins involved in this process.

The last decade has witnessed significant advance in the imaging of living systems using fluorescent markers. This progress has been primarily associated with the discovery of different spectral variants of fluorescent proteins. However, the fluorescent protein technology has its own limitations and, in some cases, the use of low-molecular-weight fluorophores is preferable. In this review, we describe the arsenal of synthetic fluorescent tools that are currently in researchers’ hands and span virtually the entire spectrum, from the UV to visible and, further, to the near-infrared region. An overview of recent advances in site-directed introduction of synthetic fluorophores into target cellular objects is provided. Application of these fluorescent probes to the solution of a wide range of biological problems, in particular, to the determination of local ion concentrations and pH in living systems, is discussed.

Background: YB-1 is a major regulator of gene expression in eukaryotic cells. In addition to its role in transcription, YB-1 plays a key role in translation and stabilization of mRNAs.

Background:The IRR is a member of the insulin receptor family that functions as a sensor of alkaline medium. Results: We have identified key motifs of IRR ectodomain that are involved in alkali sensing. Conclusion: IRR activation by alkali is a complex multipoint process. Significance: Understanding activation of IRR potentially similar to insulin receptor activation.