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Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc.

AIMS: Hyperhomocysteinaemia is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial dysfunction. Homocysteine modulates cellular methylation reactions. P66shc is a protein that promotes oxidative stress whose expression is governed by promoter methylation. We asked if homocysteine induces endothelial p66shc expression via hypomethylation of CpG dinucleotides in the p66shc promoter, and whether p66shc mediates homocysteine-stimulated endothelial cell dysfunction. METHODS AND RESULTS: Homocysteine stimulates p66shc transcription in human en

Data-Driven Computational Modeling Identifies Determinants of Glioblastoma Response to SHP2 Inhibition.

Oncogenic protein tyrosine phosphatases have long been viewed as drug targets of interest, and recently developed allosteric inhibitors of SH2 domain-containing phosphatase-2 (SHP2) have entered clinical trials. However, the ability of phosphatases to regulate many targets directly or indirectly and to both promote and antagonize oncogenic signaling may make the efficacy of phosphatase inhibition challenging to predict. Here we explore the consequences of antagonizing SHP2 in glioblastoma, a recalcitrant cancer where SHP2 has been proposed as a useful drug target. Measuring protein phosphoryla

p66Shc links alpha1-adrenergic receptors to a reactive oxygen species-dependent AKT-FOXO3A phosphorylation pathway in cardiomyocytes.

p66Shc is an adapter protein that is induced by hypertrophic stimuli and has been implicated as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. This study implicates p66Shc in an alpha(1)-adrenergtic receptor (alpha(1)-AR) pathway that requires the cooperative effects of protein kinase (PK)Cepsilon and PKCdelta and leads to AKT-FOXO3a phosphorylation in cardiomyocytes. alpha(1)-ARs promote p66Shc-YY(239/240) phosphorylation via a ROS-dependent mechanism that is localized to caveolae and requires epidermal growth factor receptor (EGFR

Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas.

Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that activated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in leiomyomas compared with myometrial tissue. We found that fifteen out of seventeen RTKs evaluated in this study were highly expressed (P < 0.02-0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher p

NO attenuates insulin signaling and motility in aortic smooth muscle cells via protein tyrosine phosphatase 1B-mediated mechanism.

OBJECTIVE: Hyperinsulinemia is a significant risk factor for the pathogenesis of vascular disease. Protein tyrosine phosphatase 1B (PTP1B) has been recognized as a modulator of insulin signaling in nonvascular cells, and we have recently reported that NO increases the activity of PTP1B in rat vascular smooth muscle cells. In the present study, we tested the hypothesis that NO attenuates insulin-stimulated cell motility via a PTP1B-mediated mechanism involving downregulation of insulin signal transduction. METHODS AND RESULTS: Treatment of primary aortic smooth muscle cells from newborn rats w

Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.

The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for "glial cell-derived neurotrophic factors") family of ligands. Mutations in the RET gene were implicated in Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by binding of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET

Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effectors to a multifunctional docking site.

The RET gene codes for a transmembrane tyrosine kinase which is a subunit of a multimeric complex that acts as a receptor for four structurally related molecules: the glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin and persephin. Germline mutations of RET cause a dominantly inherited dysgenesis of the enteric nervous system known as Hirschsprung's disease (HSCR; aganglionosis megacolon). The majority of HSCR mutations results either in a reduction of dosage of the RET protein or in the loss of RET function. Two novel distinct mutations of RET that led either to the delet

Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease.

Ret is a receptor tyrosine kinase involved in several neoplastic and developmental diseases affecting the thyroid gland and tissues of neuroectodermal origin. Different ret mutations are associated with different disease phenotypes. Gain-of-function of ret is caused by gene rearrangements in thyroid papillary carcinomas and by point mutations in multiple endocrine neoplasia (MEN) type 2A syndrome (MEN2A), in familial medullary thyroid carcinoma (FMTC), and in the more severe MEN2B syndrome. Conversely, Hirschsprung's disease (HSCR) is associated with loss of function of ret. Recently, it has b

Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling.

The IGFs promote the growth and development of the feto-placental unit during gestation, and impairment of their placental actions may result in altered intrauterine growth of the fetus. In this study, proteins involved in IGF signaling were investigated in human placentas from pregnancies complicated by intrauterine growth restriction (IUGR) compared with those from normal pregnancies. IUGR placentas exhibited 33% reduction in the protein content of IGF-I receptors, but no changes in insulin receptor protein levels. In addition, insulin receptor substrate-2 (IRS-2) protein levels were reduced

The membrane immunoglobulin receptor utilizes a Shc/Grb2/hSOS complex for activation of the mitogen-activated protein kinase cascade in a B-cell line.

Ligation of membrane immunoglobulin M (mIgM) receptor in the Ramos B-cell line induced tyrosine phosphorylation of several intracellular substrates, including the adaptor protein. Shc. Phosphorylated Shc could be seen to associate with Grb2 in a complex which included hSOS. Inasmuch as hSOS is involved in p21ras activation, we also demonstrated that mIgM ligation activated a Ras-dependent kinase cascade in which sequential activation of Raf-1 and MEK-1 culminates in the activation of p42 mitogen-activated protein (MAP) kinase (ERK-2). The tumour promoter and protein kinase C agonist, phorbol 1

Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review).

Epidermal growth factor receptor pathway substrate 8 (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which is involved in cell mitosis, differentiation and other physiological functions. Numerous studies over the last decade have demonstrated that Eps8 is overexpressed in most ubiquitous malignant tumours and subsequently binds with its receptor to activate multiple signalling pathways. Eps8 not only participates in the regulation of malignant phenotypes, such as tumour proliferation, invasion, metastasis and drug resistanc

CD47-Targeted Therapy in Cancer Immunotherapy: At a Crossroads of Promise and Challenge.

Cluster of differentiation 47 (CD47), an immune checkpoint commonly referred to as the "don't eat me" signal, plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells (DCs). Although early enthusiasm drove broad clinical development, recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential. The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategie

Role of Bruton's tyrosine kinase in B cells and malignancies.

Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor a

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… PH, pleckstrin homology; TH, TEC homology; BH, BTK homology; PRR, proline rich domain; SH2/SH3, SRC homology domains 2 and 3; Cys, cysteine-string motif Fig. 1 Domain structure of TEC kinase family members and key interacting partners of Bruton’s tyrosine kinase. a Schematic overview of the protein … PH, pleckstrin homology; TH, TEC homology; BH, BTK homology; PRR, proline rich domain; SH2/SH3, SRC homology domains 2 and 3; Cys, cysteine-string motif BTK in B cell receptor signaling The IgM BCR is essential for survival of peripheral B cells [ 34 ]. …

Molecular targeted therapy for anticancer treatment.

Since the initial clinical approval in the late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served as a fundamental backbone in precision medicine for cancer treatment. These approaches are now used clinically as first-line therapy for various types of human cancers. Compared to conventional chemotherapy, targeted therapeutic agents have efficient anticancer effects with fewer side effects. However, the emergence of drug resistanc

Протеин тиросин фосфатаза-рецептор типа каппа (ПТПРК) вернулся к рассмотрению: развивающееся понимание структуры, функций и патологии.

Protein Tyrosine Phosphataze Type Cappa (PTPRK) — мембранная тиросина фосфатаза, кодируемая часто удаляемой областью хромосомы 6q, которая играет ключевую роль в регулировании сигнала, сцепления и иммунной реакции клеток. Структурно PTPRK включает внеклеточную область, связанную с сцеплением клеток, область трансмембрана и две внутриклеточные каталитические области, ответственные за фосфатазу. В частности, PTPRK подвергается протеолитическому декольте с помощью Furin и ADAM10, в результате чего образуется внеклеточная подгруппа E и подгруппа P. Дальнейшая обработка с помощью β-Secretasa выпуск

HDAC6-an Emerging Target Against Chronic Myeloid Leukemia?

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021).

PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin-proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article "PROTACs:

DIGGER 2.0: digging into the functional impact of differential splicing on human and mouse disorders.

Changes in alternative splicing between groups or conditions contribute to protein-protein interaction rewiring, a consequence often neglected in data analysis. The web server and database DIGGER overcomes this limitation by augmenting a protein-protein interaction network with domain-domain interactions and splicing information. Here, we present DIGGER 2.0, which now features both experimental and newly added predicted domain-domain interactions. In addition to the human interactome, DIGGER 2.0 adds support for mouse as an important model organism. Additionally, we integrated the splicing ana

Тайрозин Брютона: потенциальная новая цель для неврологических расстройств.

Тирозиновая киназа Брютона (BTK) является важной частью канала сигнала B-клектора, который широко изучался при различных видах недугов. Недавние исследования расширили наши знания о его роли в метаболизме, а также в неврологических расстройствах. Она может играть важную роль в патофизиологии неврологических заболеваний, таких как множественный склероз, болезнь Альцгеймера, повреждение мозга и несколько других. Активация воспалений, главным образом NLRP3, является одним из основных механизмов, с помощью которого она поощряет воспаление мозга, связанное со старением и болезнями. В настоящем доку

Processes and therapeutic perspectives of acylation modifications of lysine and cysteine in tumors.

Acylation modification plays a crucial role in tumor progression through altering protein homeostasis and localization. However, a comprehensive summary of these processes is lacking. Protein acylation modifications are comprehensively summarized and categorized based on the amino acids that are modified. This review focuses on modifications of the lysine (acetylation, succinylation, crotonylation, malonylation, and glutarylation) and cysteine (myristoylation and palmitoylation) groups. The key enzymes involved in the occurrence and erasure of different modifications, as well as their effects