Neuregulin 1
Encyclopedia
Neuregulin 1 or NRG1 is a protein
which in humans is encoded by the NRG1 gene
. NRG1 is one of four proteins in the neuregulin
family that act on the EGFR
family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing
, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart.
that interacts with the NEU/ERBB2
receptor tyrosine kinase to increase its phosphorylation
on tyrosine
residues. It is known that an extraordinary variety of different isoforms are produced from the NRG1 gene by alternative splicing
. These isoforms include heregulins
(HRGs), glial growth factors (GGFs) and sensory and motor neuron-derived factor (SMDF). They are tissue-specifically expressed and differ significantly in their structure. The HRG isoforms all contain immunoglobulin
(Ig) and epidermal growth factor
-like (EGF-like) domains. GGF and GGF2 isoforms contain a kringle
-like sequence plus Ig and EGF-like domains; and the SMDF isoform shares only the EGF-like domain with other isoforms. The receptors for all NRG1 isoforms are the ERBB family of tyrosine kinase transmembrane receptors. Through interaction with ERBB receptors
, NRG1 isoforms induce the growth and differentiation of epithelial, neuronal, glial, and other types of cells.
interactions are thought to play a role in the pathological mechanism of schizophrenia
. A high-risk deCODE (Icelandic) haplotype was discovered in 2002 on the 5'-end of the gene. The SNP8NRG243177 allele from this haplotype was associated in 2006 with a heightened expression of the Type IV NRG1 in the brains of people suffering from schizophrenia. The protein also has the putative ability to protect the brain from damage induced by stroke. Those with a genetic variant of neuregulin 1 tended to be more creative.
There is evidence that NRG1 is a tumour suppressor gene.
with ERBB3
and LIMK1
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the NRG1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. NRG1 is one of four proteins in the neuregulin
Neuregulin
The Neuregulins are a family of four structurally-related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac...
family that act on the EGFR
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart.
Function
Neuregulin 1 (NRG1) was originally identified as a 44-kD glycoproteinGlycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
that interacts with the NEU/ERBB2
HER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
receptor tyrosine kinase to increase its phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
on tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residues. It is known that an extraordinary variety of different isoforms are produced from the NRG1 gene by alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
. These isoforms include heregulins
Neuregulin
The Neuregulins are a family of four structurally-related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac...
(HRGs), glial growth factors (GGFs) and sensory and motor neuron-derived factor (SMDF). They are tissue-specifically expressed and differ significantly in their structure. The HRG isoforms all contain immunoglobulin
Immunoglobulin domain
The immunoglobulin domain is a type of protein domain that consists of a 2-layer sandwich of between 7 and 9 antiparallel β-strands arranged in two β-sheets with a Greek key topology....
(Ig) and epidermal growth factor
Growth factor-like domain
A growth factor-like domain is a protein domain structurally related to epidermal growth factor, which has a high binding affinity for the epidermal growth factor receptor. As structural domains within larger proteins, GFLD regions commonly bind calcium ions...
-like (EGF-like) domains. GGF and GGF2 isoforms contain a kringle
Kringle domain
Kringle Domains are autonomous protein domains that fold into large loops stabilized by 3 disulfide linkages. These are important in protein-protein interactions with blood coagulation factors...
-like sequence plus Ig and EGF-like domains; and the SMDF isoform shares only the EGF-like domain with other isoforms. The receptors for all NRG1 isoforms are the ERBB family of tyrosine kinase transmembrane receptors. Through interaction with ERBB receptors
ErbB
The ErbB protein family or epidermal growth factor receptor family is a family of four structurally related receptor tyrosine kinases. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene...
, NRG1 isoforms induce the growth and differentiation of epithelial, neuronal, glial, and other types of cells.
Isoforms
At least six major types (different N termini) of neuregulin 1 are known. Six types exist in humans and rodents (type I, II and III NRG1 are expressed in excitatory and inhibitory neurons, as well as astrocytes), and some types (I and IV) can be regulated by neuronal activity.| type | aliases |
|---|---|
| I | Heregulin, NEU differentiation factor (NDF), or acetylcholine receptor inducing activity (ARIA) |
| II | Glial Growth Factor-2 (GGF2) |
| III | Sensory and motor neuron-derived factor (SMDF) |
| IV | |
| V | |
| VI |
Clinical significance
Neuregulin 1-ErbB4ERBB4
Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized....
interactions are thought to play a role in the pathological mechanism of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. A high-risk deCODE (Icelandic) haplotype was discovered in 2002 on the 5'-end of the gene. The SNP8NRG243177 allele from this haplotype was associated in 2006 with a heightened expression of the Type IV NRG1 in the brains of people suffering from schizophrenia. The protein also has the putative ability to protect the brain from damage induced by stroke. Those with a genetic variant of neuregulin 1 tended to be more creative.
There is evidence that NRG1 is a tumour suppressor gene.
Interactions
Neuregulin 1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with ERBB3
ERBB3
Receptor tyrosine-protein kinase erbB-3 is an enzyme that in humans is encoded by the ERBB3 gene.It is thought that ERBB3, when activated, becomes a substrate for dimerization and subsequent phosphorylation by ERBB1, ERBB2 and ERBB4....
and LIMK1
LIMK1
LIM domain kinase 1 is an enzyme that in humans is encoded by the LIMK1 gene.-Interactions:LIMK1 has been shown to interact with PAK1, YWHAZ, PAK4, Cofilin 1, Neuregulin 1 and Cyclin-dependent kinase inhibitor 1C.-External links:...
.
External links
- 'New way' to repair heart damage
- NRG1 rs3924999, hypothetical major gene locus of general intelligence
- Links from Schizophrenia Research ForumSchizophrenia Research ForumSchizophrenia Research Forum is a website dedicated to convey information about schizophrenia.It hosts the SzGene Database, which provides a comprehensive, unbiased and regularly updated field synopsis of genetic association studies performed in schizophrenia with hundreds of up-to-date...
:- Neuregulin, ErbB4—Levels Normal but Signaling Strengthened in Schizophrenia - 18 June 2006.
- Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits - 2 May 2007.
- Functional Neuregulin Variant Linked to Psychosis, Abnormal Brain Activation and IQ - 30 October 2006.
- Neuregulin, ErbB4 Drive Developmental Cell Fates
- Neuregulin Partner ErbB4 Spices Up Genetic Associations - 17 February 2005
- Polymorphisms and Schizophrenia—The Ups and Downs of Neuregulin Expression - 21 April 2006.
- Neuregulin Studies Suggest Synaptic Deficits in Schizophrenia - 4 June 2007