Dissecting the Kaiso binding profile in clear renal cancer cells.

Background: There has been a notable increase in interest in the transcriptional regulator Kaiso, which has been linked to the regulation of clonal hematopoiesis, myelodysplastic syndrome, and tumorigenesis. Nevertheless, there are no consistent data on the binding sites of Kaiso in vivo in the genome. Previous ChIP-seq analyses for Kaiso contradicted the accumulated data of Kaiso binding sites obtained in vitro.

Mechanisms and physiological relevance of acid-base exchange in functional units of the kidney.

This review discusses the importance of homeostasis with a particular emphasis on the acid-base (AB) balance, a crucial aspect of pH regulation in living systems. Two primary organ systems correct deviations from the standard pH balance: the respiratory system gas exchange and the kidneys proton/bicarbonate secretion and reabsorption. Focusing on kidney functions, we describe the complexity of renal architecture and its challenges for experimental research.

A Comparative Kidney Transcriptome Analysis of Bicarbonate-Loaded -Null Mice.

The maintenance of plasma pH is critical for life in all organisms. The kidney plays a critical role in acid-base regulation in vertebrates by controlling the plasma concentration of bicarbonate. The receptor tyrosine kinase IRR (insulin receptor-related receptor) is expressed in renal β-intercalated cells and is involved in alkali sensing due to its ability to autophosphorylate under alkalization of extracellular medium (pH > 7.

Pharmacogenetic Analysis of the Interaction of the Low-Molecular-Weight BDNF Mimetic Dipeptide GSB-106 with TRK Receptors.

Using TrkA or TrkB receptor gene knockout HT-22 cells, the selectivity of the interaction of the low-molecular-weight dipeptide BDNF mimetic GSB-106 (hexamethylenediamide bis(N-monosuccinyl-L-seryl-L-lysine)) with TrkB receptors was shown.

The Mechanisms of GPR55 Receptor Functional Selectivity during Apoptosis and Proliferation Regulation in Cancer Cells.

GPR55 is a non-canonical cannabinoid receptor, important for cancer proliferation. Depending on the ligand, it induces either cell proliferation or death. The objective of the study was to establish the mechanisms of this multidirectional signaling.

Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily.

Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies, including neurodegenerative diseases. The disulfide-linked dimeric structure of these receptors is unique among RTKs. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions.

Changes in the Expression of the gapdh Gene in the Organs of insrr Knockout Mice.

The most important property of a living organism is the maintenance of optimal acid-base balance and the ionic composition of the internal environment. The kidneys are one of the main pH-regulating organs in the body. Receptor tyrosine kinase IRR (an insulin receptor-related receptor) is an alkaline pH-sensor.

Insulin Receptor-Related Receptor Regulates the Rate of Early Development in .

The orphan insulin receptor-related receptor (IRR) encoded by gene is the third member of the insulin receptor family, also including the insulin receptor (IR) and the insulin-like growth factor receptor (IGF-1R). IRR is the extracellular alkaline medium sensor. In mice, is expressed only in small populations of cells in specific tissues, which contain extracorporeal liquids of extreme pH.

FLIM-Based Intracellular and Extracellular pH Measurements Using Genetically Encoded pH Sensor.

The determination of pH in live cells and tissues is of high importance in physiology and cell biology. In this report, we outline the process of the creation of SypHerExtra, a genetically encoded fluorescent sensor that is capable of measuring extracellular media pH in a mildly alkaline range. SypHerExtra is a protein created by fusing the previously described pH sensor SypHer3s with the neurexin transmembrane domain that targets its expression to the cytoplasmic membrane.

Activity-dependent conformational transitions of the insulin receptor-related receptor.

The insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor-related receptor (IRR) form a mini family of predimerized receptor-like tyrosine kinases. IR and IGF-1R bind to their peptide agonists triggering metabolic and cell growth responses. In contrast, IRR, despite sharing with them a strong sequence homology, has no peptide-like agonist but can be activated by mildly alkaline media.

Probing Structure and Function of Alkali Sensor IRR with Monoclonal Antibodies.

To study the structure and function of the pH-regulated receptor tyrosine kinase insulin receptor-related receptor (IRR), а member of the insulin receptor family, we obtained six mouse monoclonal antibodies against the recombinant IRR ectodomain. These antibodies were characterized in experiments with exogenously expressed full-length IRR by Western blotting, immunoprecipitation, and immunocytochemistry analyses. Utilizing a previously obtained set of IRR/IR chimeras with swapped small structural domains and point amino acid substitutions, we mapped the binding sites of the obtained antibodies in IRR.

The dimeric ectodomain of the alkali-sensing insulin receptor-related receptor (ectoIRR) has a droplike shape.

Insulin receptor-related receptor (IRR) is a receptor tyrosine kinase of the insulin receptor family and functions as an extracellular alkali sensor that controls metabolic alkalosis in the regulation of the acid-base balance. In the present work, we sought to analyze structural features of IRR by comparing them with those of the insulin receptor, which is its closest homolog but does not respond to pH changes. Using small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM), we investigated the overall conformation of the recombinant soluble IRR ectodomain (ectoIRR) at neutral and alkaline pH.

с-Met receptor can be activated by extracellular alkaline medium.

Receptor tyrosine kinase (RTK) Met or c-Met is a target of hepatocyte growth factor (HGF) and it plays an important role under normal and pathological conditions. Activation of Met signaling pathway is associated with several cellular processes, such as proliferation, survival, motility, angiogenesis, invasion, and metastasis. In this article, we describe the ability of Met to activate upon a mild alkali treatment.

Optimization of Heterologous Expression of Insulin Receptor-Related Receptor Ectodomain.

In this paper, we present an approach to optimize the heterologous expression of the receptor tyrosine kinase IRR, which further simplifies the purification of the IRR from the medium and increases the final yield. The approach proposed by us can find application in the biotechnological production of other large-scale recombinant proteins produced for medical purposes.

Autophosphorylation of Orphan Receptor ERBB2 Can Be Induced by Extracellular Treatment with Mildly Alkaline Media.

ErbB2 is an oncogene receptor tyrosine kinase linked to breast cancer. It is a member of the epidermal growth factor receptor (EGFR) minifamily. ErbB2 is currently viewed as an orphan receptor since, by itself, it does not bind EGF-like ligands and can be activated only when overexpressed in malignant cells or complexed with ErbB3, another member of the EGFR minifamily.

Genetically encoded fluorescent indicators for live cell pH imaging.

Background: Intracellular pH underlies most cellular processes. There is emerging evidence of a pH-signaling role in plant cells and microorganisms. Dysregulation of pH is associated with human diseases, such as cancer and Alzheimer's disease.

DeSUMOylation switches Kaiso from activator to repressor upon hyperosmotic stress.

Kaiso is a member of the BTB/POZ zinc finger family, which is involved in cancer progression, cell cycle control, apoptosis, and WNT signaling. Depending on promoter context, it may function as either a transcriptional repressor or activator. Previous studies found that Kaiso might be SUMOylated due to heat shock, but the biological significance of Kaiso SUMOylation is unclear.

Site-Directed Mutagenesis of the Fibronectin Domains in Insulin Receptor-Related Receptor.

The orphan insulin receptor-related receptor (IRR), in contrast to its close homologs, the insulin receptor (IR) and insulin-like growth factor receptor (IGF-IR) can be activated by mildly alkaline extracellular medium. We have previously demonstrated that IRR activation is defined by its extracellular region, involves multiple domains, and shows positive cooperativity with two synergistic sites. By the analyses of point mutants and chimeras of IRR with IR in, we now address the role of the fibronectin type III (FnIII) repeats in the IRR pH-sensing.

Fluorescent protein Dendra2 as a ratiometric genetically encoded pH-sensor.

Fluorescent protein Dendra2 is a monomeric GFP-like protein that belongs to the group of Kaede-like photoconvertible fluorescent proteins with irreversible photoconversion from a green- to red-emitting state when exposed to violet-blue light. In an acidic environment, photoconverted Dendra2 turns green due to protonation of the phenolic group of the chromophore with pKa of about 7.5.

BODIPY-based dye for no-wash live-cell staining and imaging.

In nonpolar solvents, hydrophobic organic fluorophores often show bright fluorescence, whereas in polar media, they usually suffer from aggregation-caused quenching (ACQ). Here, we harnessed this solvatochromic behavior of a 1,3,5,7-tetramethyl-BODIPY derivative for cell staining and applied it to live-cell imaging and flow cytometry. As opposed to commercially available dyes, this BODIPY derivative showed excellent contrast immediately after staining and did not require any wash-off.

Alkaline pH induces IRR-mediated phosphorylation of IRS-1 and actin cytoskeleton remodeling in a pancreatic beta cell line.

Secretion of mildly alkaline (pH 8.0-8.5) juice to intestines is one of the key functions of the pancreas.

Synthetic Fluorophores for Visualizing Biomolecules in Living Systems.

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.

[Behavioral Phenotype of Mice with Alkali Sensor IRR Gene Knockout].

Receptor-like tyrosine kinase IRR (the insulin receptor-related receptor) can be activated by extra- cellular alkaline media. IRR is found in organs that come in contact with liquids of extremal pH, and also in specific cells of the nervous systems where its function is not known. In this study, we analyzed the phenotype of IRR knockout mice in a series of behavioral tests.

Structural and functional analyses of the sixth site of neurexin alternative splicing.

In this study, we found the sixth site of alternative splicing (SS6) of neurexin 1a from the rat brain. This site is located between the fifth LNS and the third EGF-like domains. The insertion in the SS6 site corresponds to the 9-residue peptide VALMKADLQ, which is conserved among animals.

Determination of Alkali-Sensing Parts of the Insulin Receptor-Related Receptor Using the Bioinformatic Approach.

IRR (insulin receptor-related receptor) is a receptor tyrosine kinase belonging to the insulin receptor family, which also includes insulin receptor and IGF-IR receptor. We have previously shown that IRR is activated by extracellular fluid with pH > 7.9 and regulates excess alkali excretion in the body.