Neuregulins
Neuregulin-1
Glia Maturation Factor
Receptor, erbB-3
Genes, erbB
Oncogene Proteins v-erbB
Schwann Cells
Glycoproteins
Receptor, Epidermal Growth Factor
Nerve Growth Factors
Receptor, erbB-2
Nerve Tissue Proteins
Signal Transduction
Neu differentiation factor stimulates phosphorylation and activation of the Sp1 transcription factor. (1/275)
Neu differentiation factors (NDFs), or neuregulins, are epidermal growth factor-like growth factors which bind to two tyrosine kinase receptors, ErbB-3 and ErbB-4. The transcription of several genes is regulated by neuregulins, including genes encoding specific subunits of the acetylcholine receptor at the neuromuscular junction. Here, we have examined the promoter of the acetylcholine receptor epsilon subunit and delineated a minimal CA-rich sequence which mediates transcriptional activation by NDF (NDF-response element [NRE]). Using gel mobility shift analysis with an NRE oligonucleotide, we detected two complexes that are induced by treatment with neuregulin and other growth factors and identified Sp1, a constitutively expressed zinc finger phosphoprotein, as a component of one of these complexes. Phosphatase treatment, two-dimensional gel electrophoresis, and an in-gel kinase assay indicated that Sp1 is phosphorylated by a 60-kDa kinase in response to NDF-induced signals. Moreover, Sp1 seems to act downstream of all members of the ErbB family and thus may funnel the signaling of the ErbB network into the nucleus. (+info)An intramembrane modulator of the ErbB2 receptor tyrosine kinase that potentiates neuregulin signaling. (2/275)
The ErbB2 receptor tyrosine kinase plays a critical role in a variety of developmental processes, and its aberrant activation may contribute to the progression of some breast and ovarian tumors. ASGP2, a transmembrane glycoprotein found on the surface of the highly metastatic ascites 13762 rat mammary adenocarcinoma cell line, is constitutively associated with ErbB2 in these cells and in mammary tissue from pregnant rats. Expression studies indicate that ASGP2 interacts directly and specifically with ErbB2 through one of its epidermal growth factor-like domains and that the co-expression of the two proteins in the same cell dramatically facilitates their direct stable interaction. Ectopic expression of ASGP2 in human melanoma tumor cells potentiates the response of endogenous ErbB2 to the neuregulin-1 growth factor. These observations point to a novel intramembrane mechanism for the modulation of receptor tyrosine kinase activity. (+info)Induction of utrophin gene expression by heregulin in skeletal muscle cells: role of the N-box motif and GA binding protein. (3/275)
The modulation of utrophin gene expression in muscle by the nerve-derived factor agrin plausibly involves the trophic factor ARIA/heregulin. Here we show that heregulin treatment of mouse and human cultured myotubes caused a approximately 2.5-fold increase in utrophin mRNA levels. Transient transfection experiments with utrophin promoter-reporter gene constructs showed that this increase resulted from an enhanced transcription of the utrophin gene. In the case of the nicotinic acetylcholine receptor delta and epsilon subunit genes, heregulin was previously reported to stimulate transcription via a conserved promoter element, the N-box, which binds the multimeric Ets-related transcription factor GA binding protein (GABP). Accordingly, site-directed mutagenesis of a single N-box motif in the utrophin gene promoter abolished the transcriptional response to heregulin. In addition, overexpression of heregulin, or of the two GABP subunits in cultured myotubes, caused an N-box-dependent increase of the utrophin promoter activity. In vivo, direct gene transfer into muscle confirmed that heregulin regulates utrophin gene expression. Finally, electrophoretic mobility shift assays and supershift experiments performed with muscle extracts revealed that the N-box of the utrophin promoter binds GABP. These findings suggest that the subsynaptic activation of transcription by heregulin via the N-box motif and GABP are conserved among genes expressed at the neuromuscular junction. Because utrophin can functionally compensate for the lack of dystrophin, the elucidation of the molecular mechanisms regulating utrophin gene transcription may ultimately lead to therapies based on utrophin expression throughout the muscle fibers of Duchenne muscular dystrophy patients. (+info)Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. (4/275)
Multipotent and self-renewing neural stem cells have been isolated in culture, but equivalent cells have not yet been prospectively identified in neural tissue. Using cell surface markers and flow cytometry, we have isolated neural crest stem cells (NCSCs) from mammalian fetal peripheral nerve. These cells are phenotypically and functionally indistinguishable from NCSCs previously isolated by culturing embryonic neural tube explants. Moreover, in vivo BrdU labeling indicates that these stem cells self-renew in vivo. NCSCs freshly isolated from nerve tissue can be directly transplanted in vivo, where they generate both neurons and glia. These data indicate that neural stem cells persist in peripheral nerve into late gestation by undergoing self-renewal. Such persistence may explain the origins of some PNS tumors in humans. (+info)Processing of ARIA and release from isolated nerve terminals. (5/275)
The neuromuscular junction is a specialized synapse in that every action potential in the presynaptic nerve terminal results in an action potential in the postsynaptic membrane, unlike most interneuronal synapses where a single presynaptic input makes only a small contribution to the population postsynaptic response. The postsynaptic membrane at the neuromuscular junction contains a high density of neurotransmitter (acetylcholine) receptors and a high density of voltage-gated Na+ channels. Thus, the large acetylcholine activated current occurs at the same site where the threshold for action potential generation is low. Acetylcholine receptor inducing activity (ARIA), a 42 kD protein, that stimulates synthesis of acetylcholine receptors and voltage-gated Na+ channels in cultured myotubes, probably plays the same roles at developing and mature motor endplates in vivo. ARIA is synthesized as part of a larger, transmembrane, precursor protein called proARIA. Delivery of ARIA from motor neuron cell bodies in the spinal cord to the target endplates involves several steps, including proteolytic cleavage of proARIA. ARIA is also expressed in the central nervous system and it is abundant in the molecular layer of the cerebellum. In this paper we describe our first experiments on the processing and release of ARIA from subcellular fractions containing synaptosomes from the chick cerebellum as a model system. (+info)Binding specificities and affinities of egf domains for ErbB receptors. (6/275)
ErbB receptor activation is a complex process and is dependent upon the type and number of receptors expressed on a given cell. Previous studies with defined combinations of ErbB receptors expressed in mammalian cells have helped elucidate specific biological responses for many of the recognized gene products that serve as ligands for these receptors. However, no study has examined the binding of these ligands in a defined experimental system. To address this issue, the relative binding affinities of the egf domains of eleven ErbB ligands were measured on six ErbB receptor combinations using a soluble receptor-ligand binding format. The ErbB2/4 heterodimer was shown to bind all ligands tested with moderate to very high affinity. In contrast, ErbB3 showed much more restrictive ligand binding specificity and measurable binding was observed only with heregulin, neuregulin2beta, epiregulin and the synthetic heregulin/egf chimera, biregulin. These studies also revealed that ErbB2 preferentially enhances ligand binding to ErbB3 or ErbB4 and to a lesser degree to ErbB1. (+info)The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. (7/275)
The erbB-2/HER2 oncogene is overexpressed in a significant fraction of human carcinomas of the breast, ovary, and lung in a manner that correlates with poor prognosis. Although the encoded protein resembles several receptors for growth factors, no high affinity ligand of ErbB-2 has so far been fully characterized. However, several lines of evidence have raised the possibility that ErbB-2 can augment signal transduction initiated by binding of certain growth factors to their direct receptors. Here, we contrasted these two models of ErbB-2 function: First, examination of a large series of epidermal growth factor (EGF)-like ligands and neuregulins, including virus-encoded ligands as well as related motifs derived from the precursor of EGF, failed to detect interactions with ErbB-2 when this protein was singly expressed. Second, by using antibodies that block inter-ErbB interactions and cells devoid of surface ErbB-2, we learned that signaling by all ligands examined, except those derived from the precursor of EGF, was enhanced by the oncoprotein. These results imply that ErbB-2 evolved as a shared receptor subunit of all ErbB-specific growth factors. Thus, oncogenicity of ErbB-2 in human epithelia may not rely on the existence of a specific ligand but rather on its ability to act as a coreceptor for multiple stroma-derived growth factors. (+info)Developing Schwann cells acquire the ability to survive without axons by establishing an autocrine circuit involving insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB. (8/275)
Although Schwann cell precursors from early embryonic nerves die in the absence of axonal signals, Schwann cells in older nerves can survive in the absence of axons in the distal stump of transected nerves. This is crucially important, because successful axonal regrowth in a damaged nerve depends on interactions with living Schwann cells in the denervated distal stump. Here we show that Schwann cells acquire the ability to survive without axons by establishing an autocrine survival loop. This mechanism is absent in precursors. We show that insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB are important components of this autocrine survival signal. The secretion of these factors by Schwann cells has significant implications for cellular communication in developing nerves, in view of their known ability to regulate survival and differentiation of other cells including neurons. (+info)Neuregulins are a family of growth factors that play important roles in the development and maintenance of the nervous system. They bind to and activate receptors known as ErbB receptors, which are tyrosine kinase receptors. Neuregulins are involved in the regulation of various cellular processes, including proliferation, differentiation, migration, and survival.
There are several different forms of neuregulins, which are produced by alternative splicing of a single gene. These forms include heregulin, glial growth factor, and neu differentiation factor. Neuregulins are produced by various cell types in the nervous system, including neurons and glial cells. They are involved in the development and maintenance of the nervous system, including the formation of synapses, the regulation of myelination, and the survival of neurons.
Dysregulation of neuregulin signaling has been implicated in various neurological disorders, including schizophrenia, Alzheimer's disease, and epilepsy.
Neuregulin-1 (NRG-1) is a growth factor that belongs to the neuregulin family and is involved in the development and function of the nervous system. It is a protein that is encoded by the NRG1 gene and is expressed in various tissues, including the brain. NRG-1 plays important roles in the regulation of neuronal survival, migration, differentiation, and synaptic plasticity. It acts as a ligand for the ErbB family of receptor tyrosine kinases, which are involved in intracellular signaling pathways that control various cellular processes. Abnormalities in NRG-1 signaling have been implicated in several neurological and psychiatric disorders, including schizophrenia, bipolar disorder, and Alzheimer's disease.
Glia maturation factor (GMF) is a protein that belongs to the family of non-catalytic leucine-rich repeat and immunoglobulin-like domain-containing Nogo receptor-interacting proteins (NLRs). GMF is primarily expressed in glial cells in the central nervous system. It plays a crucial role in regulating cytoskeletal dynamics, particularly actin polymerization and depolymerization, which are essential for various cellular processes such as cell motility, division, and differentiation.
GMF has been shown to interact with the actin-depolymerizing factor cofilin and regulate its activity by controlling its phosphorylation state. Specifically, GMF inhibits cofilin's ability to sever and depolymerize actin filaments, thereby promoting actin polymerization and stabilization of the cytoskeleton.
In addition to its role in cytoskeletal regulation, GMF has been implicated in various neurological disorders, including Alzheimer's disease, Parkinson's disease, and spinal cord injury. However, further research is needed to fully understand the molecular mechanisms underlying these associations.
ErбB-3, also known as HER3 or EGFR3, is a type of receptor tyrosine kinase (RTK) that belongs to the ErbB family of receptors. It is a single-pass transmembrane protein composed of an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyrosine kinase domain.
ErбB-3 plays a crucial role in regulating various cellular processes such as proliferation, differentiation, survival, and migration. However, unlike other ErbB receptors, ErbB-3 lacks intrinsic tyrosine kinase activity due to the presence of several mutations in its kinase domain. Therefore, it requires heterodimerization with other ErbB family members, such as ErbB2 or ErbB4, to become activated and initiate downstream signaling pathways.
The primary ligand for ErbB-3 is neuregulin 1 (NRG1), which binds to the extracellular domain of ErbB-3 and induces its dimerization with other ErbB receptors. This leads to the activation of several downstream signaling pathways, including the PI3K/Akt and MAPK pathways, which promote cell survival, proliferation, and migration.
Abnormal regulation of ErbB-3 has been implicated in various human cancers, such as breast, ovarian, lung, and colon cancer. Overexpression or mutations in ErbB-3 have been shown to contribute to tumor growth, progression, and resistance to therapy. Therefore, targeting ErbB-3 is an active area of research for the development of novel cancer therapies.
ERBB genes (also known as HER or human epidermal growth factor receptor) are a family of genes that encode for transmembrane receptor tyrosine kinases. These receptors play crucial roles in various cellular processes such as proliferation, differentiation, and survival. The ERBB gene family includes four members: EGFR (ERBB1), ERBB2 (HER2/neu), ERBB3 (HER3), and ERBB4 (HER4). Dysregulation of these genes has been implicated in several human cancers, making them attractive targets for cancer therapy.
The oncogene proteins v-erbB are derived from the erbB oncogene, which is a retroviral oncogene first discovered in avian erythroblastosis viruses (AEV). The erbB oncogene is homologous to the human epidermal growth factor receptor 2 (HER2/erbB-2) gene, which encodes a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation.
The v-erbB oncogene protein is a truncated and mutated version of the normal EGFR/erbB-1 receptor, which has lost its extracellular ligand-binding domain and gained constitutive tyrosine kinase activity. This results in uncontrolled cell growth and division, leading to the development of cancer.
The v-erbB oncogene protein has been extensively studied as a model system for understanding the molecular mechanisms of oncogenesis and has provided valuable insights into the regulation of cell growth and differentiation. Additionally, the study of v-erbB and other oncogenes has led to the development of targeted cancer therapies that inhibit the activity of these aberrant proteins and slow or stop the growth of cancer cells.
Schwann cells, also known as neurolemmocytes, are a type of glial cell that form the myelin sheath around peripheral nervous system (PNS) axons, allowing for the rapid and efficient transmission of nerve impulses. These cells play a crucial role in the maintenance and function of the PNS.
Schwann cells originate from the neural crest during embryonic development and migrate to the developing nerves. They wrap around the axons in a spiral fashion, forming multiple layers of myelin, which insulates the nerve fibers and increases the speed of electrical impulse transmission. Each Schwann cell is responsible for myelinating a single segment of an axon, with the gaps between these segments called nodes of Ranvier.
Schwann cells also provide structural support to the neurons and contribute to the regeneration of injured peripheral nerves by helping to guide the regrowth of axons to their targets. Additionally, Schwann cells can participate in immune responses within the PNS, such as releasing cytokines and chemokines to recruit immune cells during injury or infection.
Glycoproteins are complex proteins that contain oligosaccharide chains (glycans) covalently attached to their polypeptide backbone. These glycans are linked to the protein through asparagine residues (N-linked) or serine/threonine residues (O-linked). Glycoproteins play crucial roles in various biological processes, including cell recognition, cell-cell interactions, cell adhesion, and signal transduction. They are widely distributed in nature and can be found on the outer surface of cell membranes, in extracellular fluids, and as components of the extracellular matrix. The structure and composition of glycoproteins can vary significantly depending on their function and location within an organism.
The Epidermal Growth Factor Receptor (EGFR) is a type of receptor found on the surface of many cells in the body, including those of the epidermis or outer layer of the skin. It is a transmembrane protein that has an extracellular ligand-binding domain and an intracellular tyrosine kinase domain.
EGFR plays a crucial role in various cellular processes such as proliferation, differentiation, migration, and survival. When EGF (Epidermal Growth Factor) or other ligands bind to the extracellular domain of EGFR, it causes the receptor to dimerize and activate its intrinsic tyrosine kinase activity. This leads to the autophosphorylation of specific tyrosine residues on the receptor, which in turn recruits and activates various downstream signaling molecules, resulting in a cascade of intracellular signaling events that ultimately regulate gene expression and cell behavior.
Abnormal activation of EGFR has been implicated in several human diseases, including cancer. Overexpression or mutation of EGFR can lead to uncontrolled cell growth and division, angiogenesis, and metastasis, making it an important target for cancer therapy.
Nerve Growth Factors (NGFs) are a family of proteins that play an essential role in the growth, maintenance, and survival of certain neurons (nerve cells). They were first discovered by Rita Levi-Montalcini and Stanley Cohen in 1956. NGF is particularly crucial for the development and function of the peripheral nervous system, which connects the central nervous system to various organs and tissues throughout the body.
NGF supports the differentiation and survival of sympathetic and sensory neurons during embryonic development. In adults, NGF continues to regulate the maintenance and repair of these neurons, contributing to neuroplasticity – the brain's ability to adapt and change over time. Additionally, NGF has been implicated in pain transmission and modulation, as well as inflammatory responses.
Abnormal levels or dysfunctional NGF signaling have been associated with various medical conditions, including neurodegenerative diseases (e.g., Alzheimer's and Parkinson's), chronic pain disorders, and certain cancers (e.g., small cell lung cancer). Therefore, understanding the role of NGF in physiological and pathological processes may provide valuable insights into developing novel therapeutic strategies for these conditions.
"ErbB-2" is also known as "HER2" or "human epidermal growth factor receptor 2." It is a type of receptor tyrosine kinase (RTK) found on the surface of some cells. ErbB-2 does not bind to any known ligands, but it can form heterodimers with other ErbB family members, such as ErbB-3 and ErbB-4, which do have identified ligands. When a ligand binds to one of these receptors, it causes a conformational change that allows the ErbB-2 receptor to become activated through transphosphorylation. This activation triggers a signaling cascade that regulates cell growth, differentiation, and survival.
Overexpression or amplification of the ERBB2 gene, which encodes the ErbB-2 protein, is observed in approximately 20-30% of breast cancers and is associated with a more aggressive disease phenotype and poorer prognosis. Therefore, ErbB-2 has become an important target for cancer therapy, and several drugs that target this receptor have been developed, including trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta).
Nerve tissue proteins are specialized proteins found in the nervous system that provide structural and functional support to nerve cells, also known as neurons. These proteins include:
1. Neurofilaments: These are type IV intermediate filaments that provide structural support to neurons and help maintain their shape and size. They are composed of three subunits - NFL (light), NFM (medium), and NFH (heavy).
2. Neuronal Cytoskeletal Proteins: These include tubulins, actins, and spectrins that provide structural support to the neuronal cytoskeleton and help maintain its integrity.
3. Neurotransmitter Receptors: These are specialized proteins located on the postsynaptic membrane of neurons that bind neurotransmitters released by presynaptic neurons, triggering a response in the target cell.
4. Ion Channels: These are transmembrane proteins that regulate the flow of ions across the neuronal membrane and play a crucial role in generating and transmitting electrical signals in neurons.
5. Signaling Proteins: These include enzymes, receptors, and adaptor proteins that mediate intracellular signaling pathways involved in neuronal development, differentiation, survival, and death.
6. Adhesion Proteins: These are cell surface proteins that mediate cell-cell and cell-matrix interactions, playing a crucial role in the formation and maintenance of neural circuits.
7. Extracellular Matrix Proteins: These include proteoglycans, laminins, and collagens that provide structural support to nerve tissue and regulate neuronal migration, differentiation, and survival.
Signal transduction is the process by which a cell converts an extracellular signal, such as a hormone or neurotransmitter, into an intracellular response. This involves a series of molecular events that transmit the signal from the cell surface to the interior of the cell, ultimately resulting in changes in gene expression, protein activity, or metabolism.
The process typically begins with the binding of the extracellular signal to a receptor located on the cell membrane. This binding event activates the receptor, which then triggers a cascade of intracellular signaling molecules, such as second messengers, protein kinases, and ion channels. These molecules amplify and propagate the signal, ultimately leading to the activation or inhibition of specific cellular responses.
Signal transduction pathways are highly regulated and can be modulated by various factors, including other signaling molecules, post-translational modifications, and feedback mechanisms. Dysregulation of these pathways has been implicated in a variety of diseases, including cancer, diabetes, and neurological disorders.