Intrinsic Tyrosine Kinase Activity Research Articles

Arsenic-induced IGF-1 signaling impairment and neurite shortening: The protective roles of IGF-1 through the PI3K/Akt axis.

We recently reported that arsenic caused insulin resistance in differentiated human neuroblastoma SH-SY5Y cells. Herein, we further investigated the effects of sodium arsenite on IGF-1 signaling, which shares downstream signaling with insulin. A time-course experiment revealed that sodium arsenite began to decrease IGF-1-stimulated Akt phosphorylation on Day 3 after treatment, indicating that prolonged sodium arsenite treatment disrupted the neuronal IGF-1 response. Additionally, sodium arsenite decreased IGF-1-stimulated tyrosine phosphorylation of the IGF-1 receptor β (IGF-1Rβ) and its downstream target, insulin receptor substrate 1 (IRS1). These results suggested that sodium arsenite impaired the intrinsic tyrosine kinase activity of IGF-1Rβ, ultimately resulting in a reduction in tyrosine-phosphorylated IRS1. Sodium arsenite also reduced IGF-1 stimulated tyrosine phosphorylation of insulin receptor β (IRβ), indicating the potential inhibition of IGF-1R/IR crosstalk by sodium arsenite. Interestingly, sodium arsenite also induced neurite shortening at the same concentrations that caused IGF-1 signaling impairment. A 24-h IGF-1 treatment partially rescued neurite shortening caused by sodium arsenite. Moreover, the reduction in Akt phosphorylation by sodium arsenite was attenuated by IGF-1. Inhibition of PI3K/Akt by LY294002 diminished the protective effects of IGF-1 against sodium arsenite-induced neurite retraction. Together, our findings suggested that sodium arsenite-impaired IGF-1 signaling, leading to neurite shortening through IGF-1/PI3K/Akt.

Pharmacogenetic and liquid biopsy: The new tools of precision medicine in cancer

The main difficulty in the treatment of cancer lies in the already known mechanism of resistance to conventional chemotherapy. It is mainly due to the expression of the multidrug transport systems known as ABC transporters, both in neoplastic cells and in excretory organs that reduce the chemotherapeutic concentration. The cancer cell proliferation by activation of growth factor receptors induces their intrinsic tyrosine kinase activity, and their intracellular signaling pathways involved in such activation. Tumor proliferation can respond to the direct action of growth factors on their respective receptors, or due to somatic mutations in different steps of their signaling pathway, in an independent manner of growth factor stimulus. Pharmacogenetics studies have been performed to identify these drivers’ mutations and their detection enables targeted inhibitory therapies against their abnormal proteins. The design of new molecules capable of inhibiting these signals has opened a new line of treatment for each type of tumor, thereby enabling tumor growth control and giving rise to the precision medicine approach. It is possible that mutations of sensitive and resistant to these targeted therapies coexist in the same tumor, from the start of therapy or as a consequence of the first-line treatment. The mutations in circulating DNA in body fluids, which are detected and quantified by droplet digital polymerase chain reaction-assisted liquid biopsy, are the ideal biomarkers for the evaluation of pharmacological response, which is crucial for facilitating the change of therapeutic strategy involving second- or third-generation drugs. The quantification of these mutations can be used to assess minimal residual disease in the therapeutic follow-up of each case.

Neddylation of HER2 Inhibits its Protein Degradation and promotes Breast Cancer Progression.

HER2 is a transmembrane receptor with intrinsic tyrosine kinase activity that is overexpressed in almost 25% of human breast cancers. Here, we report that the neddylation of HER2 is a new post-translational modification that controls its expression and oncogenic activity in human breast cancer. Two critical members in the neddylation pathway, NEDD8 and NEDD8-activating enzyme E1 subunit 1 (NAE1), are detected in human breast specimens. Overexpressed NEDD8 and NAE1 are positively correlated with HER2 expression in human breast cancer. Subsequent structure and function experiments show that HER2 directly interacts with NEDD8 and NAE1, whereas HER2 protein expression is decreased by neddylation depletion. Mechanistically, neddylation inhibition promotes the degradation of HER2 protein by improving its ubiquitination. HER2 overexpression abrogates neddylation depletion-triggered cell growth suppression. The inhibition of neddylation synergized with trastuzumab significantly suppresses growth of HER2 positive breast cancer. Collectively, this study demonstrates a previously undiscovered role of NEDD8-dependent HER2 neddylation promotes tumor growth in breast cancer.

HULC targets the IGF1R–PI3K-AKT axis in trans to promote breast cancer metastasis and cisplatin resistance

Insulin-like growth factor I receptor (IGF1R) is frequently upregulated in breast cancer. Due to its intrinsic tyrosine kinase activity, aberrant activation of the IGF1R signaling axis may enhance tumor cell proliferation and cancer stemness, causing tumor relapse, metastasis and resistance to chemotherapy. We utilized a chromatin RNA in situ reverse transcription (CRIST) approach to characterize molecular factors that regulate the IGF1R network. We identified lncRNA HULC (Highly Upregulated in Liver Cancer) as a key trans-regulator of IGF1R in breast cancer cells. Loss of HULC suppressed the expression of IGF1R and the activation of its downstream PI3K/AKT pathway, while HULC overexpression activated the axis in breast cancer cells. Using a transcription-associated trap (RAT) assay, we demonstrated that HULC functioned as a nuclear lncRNA and epigenetically activated IGF1R by directly binding to the intragenic regulatory elements of the gene, orchestrating intrachromosomal interactions, and promoting histone H3K9 acetylation. The activated HULC-IGF1R/PI3K/AKT pathway mediated tumor resistance to cisplatin through the increased expression of cancer stemness markers, including NANOG, SOX2, OCT4, CD44 and ALDH1A1. In immunodeficient mice, stimulation of the HULC-IGF1R pathway promoted tumor metastasis. These data suggest that HULC may be a new epigenetic target for IGF1R axis-targeted therapeutic intervention.

Receptor Tyrosine Kinases Mediated Cell Signalling Pathways

A small number of signalling pathways, including receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), are activated by plasma membrane receptors in order for cells to respond to external cues. In addition to transmitting, these pathways also process, encode, and integrate both internal and external signals. In recent years, it has become clear that different spatio-temporal activation profiles of the same set of signalling proteins lead to different gene-expression patterns and various physiological responses. These findings suggest that the precise temporal control and relative spatial distribution of activated signal transducers are necessary for important cellular decisions such as cytoskeletal reorganisation, cell-cycle checkpoints, and cell death (apoptosis). Due to their crucial function in the control of embryogenesis, cell survival, motility, proliferation, differentiation, glucose metabolism, and apoptosis, RTK-mediated signalling pathways have drawn a lot of attention from scientists. A significant number of serious human diseases, including diabetes, cancer, chronic inflammatory syndromes, and developmental defects, are caused by RTK signalling dysfunction. RTKs undergo allosteric transitions (the insulin receptor, for instance) or dimerization in response to stimulation, which activates the intrinsic tyrosine-kinase activity. Numerous cytoplasmic proteins receive a biochemical signal from subsequent phosphorylation of numerous tyrosine residues on the receptor, which causes them to move to the cell surface. Through intricate biochemical circuits of protein-protein interactions and covalent modification cascades, the resulting cellular reactions take place. The earlier theories of discrete linear pathways, which connected extracellular signals to the expression of particular genes, have been replaced by an emerging picture of interconnected signalling networks, raising concerns about the specificity of signal-response events. In actuality, all RTK-mediated pathways share a common protein complement that mediates signal transduction downstream of RTKs. The expression of nuclear transcription factors is induced by the activation of kinase and phosphatase cascades, such as the mitogen-activated protein kinase (MAPK) cascades, which are both activated by GPCRs and RTKs. There is no single protein or gene that determines the specificity of a signal for any given receptor pathway. Instead, the temporal and spatial dynamics of the components of downstream signalling control specificity. A classic example is the distinctive biological response to EGF and nerve growth factor stimulation of PC12 cell lines (NGF). Cell proliferation is temporarily induced by EGF, whereas cell differentiation is temporarily triggered by sustained MAPK activation by NGF. However, there are many variables that affect how MAPK cascades behave. Depending heavily on their subcellular localization and their recruitment to scaffold proteins, MAPK cascades can produce oscillations, abrupt switches, bistable dynamics.

Correlation Epidermal Growth Factor Receptor Mutation with Non-small Cell Lung Cancer in Passive Smokers: A Review

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with an extracellular epidermal growth factor binding domain and an intracellular tyrosine kinase domain through signaling pathways to regulate cellular proliferation. Epidermal growth factor receptor binding to its ligand will result in autophosphorylation by intrinsic tyrosine kinase activity, thereby triggering multiple signal transduction cascades. Constant or sustained activation of these downstream target sequences is thought to result in a more aggressive tumor phenotype. Mutations in EGFR are associated with non-small cell lung cancer in passive smokers.

It Takes More than Two to Tango: Complex, Hierarchal, and Membrane-Modulated Interactions in the Regulation of Receptor Tyrosine Kinases.

Simple SummaryReceptor tyrosine kinases probably constitute the most important subfamily of transmembrane receptors with respect to their role in regulating the balance between cell proliferation and cell death. Their activation involves ligand-induced conformational changes followed by their dimerization. Although this simple mechanism is still known to lie at the root of the process, the picture is complicated by the involvement of several receptor domains in the dimerization and the formation of larger receptor aggregates. Both clustering and activation are influenced by lipid-mediated interactions of the plasma membrane with the receptors. The intricate regulation of receptor activation is subverted in cancer that involves not only alterations in receptor structure and expression but also changes in lipid composition of the cell membrane. This paper provides a concise overview of how these biophysical aspects of transmembrane signaling regulate this important process in health and disease.The search for an understanding of how cell fate and motility are regulated is not a purely scientific undertaking, but it can also lead to rationally designed therapies against cancer. The discovery of tyrosine kinases about half a century ago, the subsequent characterization of certain transmembrane receptors harboring tyrosine kinase activity, and their connection to the development of human cancer ushered in a new age with the hope of finding a treatment for malignant diseases in the foreseeable future. However, painstaking efforts were required to uncover the principles of how these receptors with intrinsic tyrosine kinase activity are regulated. Developments in molecular and structural biology and biophysical approaches paved the way towards better understanding of these pathways. Discoveries in the past twenty years first resulted in the formulation of textbook dogmas, such as dimerization-driven receptor association, which were followed by fine-tuning the model. In this review, the role of molecular interactions taking place during the activation of receptor tyrosine kinases, with special attention to the epidermal growth factor receptor family, will be discussed. The fact that these receptors are anchored in the membrane provides ample opportunities for modulatory lipid–protein interactions that will be considered in detail in the second part of the manuscript. Although qualitative and quantitative alterations in lipids in cancer are not sufficient in their own right to drive the malignant transformation, they both contribute to tumor formation and also provide ways to treat cancer. The review will be concluded with a summary of these medical aspects of lipid–protein interactions.

Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases.

Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical STAT signaling pathways, upon binding with their cognate receptors, cytokines lead to a caspase of Janus kinases (JAKs) and STATs tyrosine phosphorylation and activation. Besides receptor-associated tyrosine kinases JAKs, receptors with intrinsic tyrosine kinase activities, G-protein coupled receptors, and non-receptor tyrosine kinases can also activate STATs through tyrosine phosphorylation or, alternatively, other post-translational modifications. Activated STATs translocate into the nucleus and mediate the transcription of specific genes, thus mediating the progression of various renal diseases. Non-canonical STAT pathways consist of preassembled receptor complexes, preformed STAT dimers, unphosphorylated STATs (U-STATs), and non-canonical functions including mitochondria modulation, microtubule regulation and heterochromatin stabilization. Most studies targeting STAT signaling pathways have focused on canonical pathways, but research extending into non-canonical STAT pathways would provide novel strategies for treating renal diseases. In this review, we will introduce both canonical and non-canonical STAT pathways and their roles in a variety of renal diseases.

Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies.

Receptor tyrosine kinase ROR1 plays an essential role in embryogenesis and is overexpressed in many types of malignant tumors. Studies have demonstrated that it plays an important role in oncogenesis by activating cell survival signaling events, particularly the non-canonical WNT signaling pathway. Antibody-based immunotherapies targeting ROR1 have been developed and evaluated in preclinical and clinical studies with promising outcomes. However, small molecule inhibitors targeting ROR1 are underappreciated because of the initial characterization of ROR1 as a peusdokinase. The function of ROR1 as a tyrosine kinase remains poorly understood, although accumulating evidence have demonstrated its intrinsic tyrosine kinase activity. In this review, we analyzed the structural and functional features of ROR1 and discussed therapeutic strategies targeting this kinase.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics.

Epidermal Growth Factor Receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity, is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that triggers tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells, thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Furthermore, the mechanisms of action of potential molecules at various stages of drug development, as well as clinically approved drugs for breast cancer treatment, are illustrated.

Jumonji domain-containing protein 6 protein and its role in cancer.

The jumonji domain‐containing protein 6 (JMJD6) is a Fe(II)‐ and 2‐oxoglutarate (2OG)‐dependent oxygenase that catalyses lysine hydroxylation and arginine demethylation of histone and non‐histone peptides. Recently, the intrinsic tyrosine kinase activity of JMJD6 has also been reported. The JMJD6 has been implicated in embryonic development, cellular proliferation and migration, self‐tolerance induction in the thymus, and adipocyte differentiation. Not surprisingly, abnormal expression of JMJD6 may contribute to the development of many diseases, such as neuropathic pain, foot‐and‐mouth disease, gestational diabetes mellitus, hepatitis C and various types of cancer. In the present review, we summarized the structure and functions of JMJD6, with particular emphasis on the role of JMJD6 in cancer progression.

The Role of c-ERBB2(Her-2) and P53 in Differentiating Low Grade from High Grade Urothelial Carcinoma of Urinary Bladder

Background: Urothelial carcinoma of the urinary bladder, represents 90% of all primary tumors of this organ, and one of the most common ten malignancy in Iraq and world wide. These tumors can range from low grade papillary neoplasms to less frequent more aggressive and invasive solid tumors. More than 70% of superficial tumors recur, and about one-third of the patients have tumor progression, which can affect the quality of their life HER-2\neu receptor as an important growth factor . This receptor possesses intrinsic tyrosine kinase activity and all members of this family are frequently overexpressed and \or their respective genes are amplified in human neoplastic tissue . Its overexpression has been associated with high grade and advanced stage of bladder carcinoma specially TCC. Altered expression of the p53 gene has also been associated with transitional cell carcinoma. Materials and Methods: 62 patients with TCC were included in this study and conducted in the Department of Pathology, Faculty of Medicine, Kufa University during the period from January 2012 through April 2013. EnVision method (polymer based immunohistochemistry) was used for the immunohistochemical detection of p53 and Her_2/neu. Results: HER-2\neu overexpression was found in 62.9% of bladder carcinoma , and no expression in benign bladder lesions (cystitis) was detected , (P value < 0.05) . HER-2\neu overexpression and its intensity were well correlated to grade of tumor indicating that HER-2\neu positive bladder carcinoma are biologically aggressive and detected more frequent in grade III than grade I or grade II (P value < 0.05, R = 0.0181).P53 was expressed in (66.12%) of bladder carcinoma , and no expression in benign bladder lesions (cystitis) was detected , (P value < 0.05) . P53 overexpression and its intensity were well correlated to grade of tumor indicating that P53 positive bladder carcinoma are biologically aggressive and detected more frequent in grade III than grade I or grade II (P value < 0.05, R = 0.0821). Conclusions: From the above results we concluded that p53 and Her_2/neu over-expression play an important role in pathogenesis of urothelial carcinoma evolution, as their positivity associated with higher tumor grade.

FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications.

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.

The role of SRC family kinases in FLT3 signaling.

The receptor tyrosine kinase FLT3 is expressed almost exclusively in the hematopoietic compartment. Binding of its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. This leads to autophosphorylation of FLT3 on several tyrosine residues which constitute high affinity binding sites for signal transduction molecules. Recruitment of these signal transduction molecules to FLT3 leads to the activation of several signal transduction pathways that regulate cell survival, cell proliferation and differentiation. Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC. They are also involved in negative regulation of signaling through phosphorylation of the ubiquitin E3 ligase CBL. Initially studied as the SFKs, as if they were a homogenous group of kinases, recent data suggest that each SFK has its own specific signaling capabilities where some are involved in positive signaling, while others are involved in negative signaling. This review discusses some recent insights into how SFKs are involved in FLT3 signaling.

JMJD6 regulates histone H2A.X phosphorylation and promotes autophagy in triple-negative breast cancer cells via a novel tyrosine kinase activity.

Overexpression of Jumonji domain-containing 6 (JMJD6) has been reported to be associated with more aggressive breast cancer characteristics. However, the precise role of JMJD6 in breast cancer development remains unclear. Here, we demonstrate that JMJD6 has intrinsic tyrosine kinase activity and can utilize ATP and GTP as phosphate donors to phosphorylate Y39 of histone H2A.X (H2A.XY39ph). High JMJD6 levels promoted autophagy in triple negative breast cancer (TNBC) cells by regulating the expression of autophagy-related genes. The JMJD6-H2A.XY39ph axis promoted TNBC cell growth via the autophagy pathway. We show that combined inhibition of JMJD6 kinase activity and autophagy efficiently decreases TNBC growth. Together, these findings suggest an effective strategy for TNBC treatment.

Deficiency of the Wnt receptor Ryk causes multiple cardiac and outflow tract defects

Ryk is a member of the receptor tyrosine kinase (RTK) family of proteins that control and regulate cellular processes. It is distinguished by binding Wnt ligands and having no detectable intrinsic protein tyrosine kinase activity suggesting Ryk is a pseudokinase. Here, we show an essential role for Ryk in directing morphogenetic events required for normal cardiac development through the examination of Ryk-deficient mice. We employed vascular corrosion casting, vascular perfusion with contrast dye, and immunohistochemistry to characterize cardiovascular and pharyngeal defects in Ryk−/− embryos. Ryk−/− mice exhibit a variety of malformations of the heart and outflow tract that resemble human congenital heart defects. This included stenosis and interruption of the aortic arch, ventriculoarterial malalignment, ventricular septal defects and abnormal pharyngeal arch artery remodelling. This study therefore defines a key intersection between a subset of growth factor receptors involved in planar cell polarity signalling, the Wnt family and mammalian cardiovascular development.

A link between a synonymous SNP and the clinical response to tyrosine kinase inhibitors.

Epidermal growth factor receptor (EGFR) is a member of the large receptor tyrosine kinase (RTK) family. Upon binding to corresponding growth factor ligands, EGFR dimerizes, and triggers intrinsic protein tyrosine kinase activity that regulates cell growth, proliferation, differentiation and survival (1,2). EGFR consists of an extracellular ligand-binding domain, a single transmembrane region and an intracellular tyrosine kinase domain (3). Phosphorylated EGFR stimulates many downstream signaling pathways by recruitment of effector proteins.

Detection of MET amplification in gastroesophageal tumor specimens using IQFISH.

The gene mesenchymal epithelial transition factor (MET) is a proto-oncogene that encodes a transmembrane receptor with intrinsic tyrosine kinase activity known as Met or cMet. MET is found to be amplified in several human cancers including gastroesophageal cancer. Here we report the MET amplification prevalence data from 159 consecutive tumor specimens from patients with gastric (G), gastroesophageal junction (GEJ) and esophageal (E) adenocarcinoma, using a novel fluorescence in situ hybridization (FISH) assay, MET/CEN-7 IQFISH Probe Mix [an investigational use only (IUO) assay]. MET amplification was defined as a MET/CEN-7 ratio ≥2.0. Furthermore, the link between the MET signal distribution and amplification status was investigated. The prevalence of MET amplification was found to be 6.9%. The FISH assay demonstrated a high inter-observer reproducibility. The inter-observer results showed a 100% overall agreement with respect to the MET status (amplified/non-amplified). The inter-observer CV was estimated to 11.8% (95% CI: 10.2-13.4). For the signal distribution, the inter-observer agreement was reported to be 98.7%. We also report an association of MET amplification and a unique signal distribution pattern in the G/GEJ/E tumor specimens. We found that the prevalence of MET amplification was markedly higher in tumors specimens with a heterogeneous (66.7%) versus homogeneous (2.0%) signal distribution. Furthermore, specimens with a heterogeneous signal distribution had a statically significantly higher median MET/CEN-7 ratio (2.35 versus 1.04; P<0.0001). The novel FISH assay showed a high inter-observer reproducibility both with respect to amplification status and signal distribution. Based on the finding in the study it is suggested that MET amplification mainly is associated with tumor cells that is represented by a heterogonous growth pattern.

The complex roles of STAT3 and STAT5 in maintaining redox balance: Lessons from STAT-mediated xCT expression in cancer cells

STAT3 and STAT5 mediate diverse cellular processes, transcriptionally regulating gene expression and interacting with cytoplasmic proteins. Their canonical activity is stimulated by cytokines/growth factors through JAK-STAT signaling. As targets of oncogenes with intrinsic tyrosine kinase activity, STAT3 and STAT5 become constitutively active in hematologic neoplasms and solid tumors, promoting cell proliferation and survival and modulating redox homeostasis. This review summarizes reactive oxygen species (ROS)-regulated STAT activation and how STATs influence ROS production. ROS-induced effects on post-translational modifications are presented, and STAT3/5-mediated regulation of xCT, a redox-sensitive target up-regulated in numerous cancers, is discussed with regard to transcriptional cross-talk.

VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function.

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are key regulators of vascular development in vertebrates. Their activation is regulated through a family of secreted glycoproteins, the vascular endothelial growth factors (VEGFs). Expression, proteolytic processing, and diffusion range of VEGF proteins need to be tightly regulated, due to their crucial roles in development. While some VEGFs form concentration gradients across developing tissues and act as morphogenes, others function as inhibitors of receptor activation and downstream signaling. Ligand-induced receptor dimerization leads to activation of the intrinsic tyrosine kinase activity, which results in autophosphorylation of the receptors and in turn triggers the recruitment of interacting proteins as well as the initiation of downstream signaling. Although many biochemical details of VEGFR signaling have been revealed, the in vivo relevance of certain signaling aspects still remains to be demonstrated. Here, we highlight basic principles of VEGFR signaling and discuss its crucial role during development of the vascular system in mammals.