ErbB
Encyclopedia
The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinase
s. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis
and Alzheimer's Disease
.
In mice loss of signaling by any member of the ErbB family results in embryo
nic lethality with defects in organs including the lung
s, skin
, heart
, and brain
. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor
. ErbB-1 and ErbB-2 are found in many human cancer
s, and their excessive signaling may be critical factors in the development and malignancy of these tumor
s.
v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain.
region or ectodomain that contains approximately 620 amino acid
s, a single transmembrane-spanning region, and a cytoplasmic tyrosine kinase
domain. The extracellular region of each family member is made up of four subdomains, L1, CR1, L2, and CR2, where "L" signifies a leucine
-rich repeat domain and "CR" a cysteine
-rich region. These subdomains are shown in blue (L1), green (CR1), yellow (L2), and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV, respectively.
The figure below was created using the pdb
files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4).
, heterodimers
, and possibly higher-order oligomers upon activation by a subset of potential growth factor
ligands
.
There are 11 growth factor
s that activate ErbB receptors. The ability of each growth factor to activate each of the ErbB receptors is shown in the table below, + and - signifying ability and inability to activate each of the ErbB receptors respectively.
When not bound to a ligand the extracellular regions of ErbB-1, -3, and -4 are found in a 'tethered' conformation in which a 10-amino-acid-long dimerisation arm is unable to mediate monomer-monomer interactions. In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2, the dimerisation arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible. The consequence of ectodomain dimerisation is the positioning of two cytoplasmic domain such that transphosphorylation
of specific tyrosine
, serine
, and threonine
amino acids can occur within the cytoplasmic domain of each ErbB. At least 10 specific tyrosines, 7 serines, and 2 threonines have been identified within the cytoplamic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerisation. Although a number of potential phosphorylation sites exist, upon dimerisation only one or much more rarely two of these sites are phosphorylated at any one time.
, cetuximab
, gefitinib
, erlotinib
are used to inhibit it. It has recently been shown that acquired resistance to cetuximab and gefitinib can be linked to hyperactivity of ErbB-3.
This is linked to an acquired overexpression of c-MET
, which phosphorylates ErbB-3, which in turn activates the Akt pathway.
ErbB-2 (HER-2) is often overexpressed in breast cancer. The drug Trastuzumab (Herceptin) targets this receptor. Only one-third of the women respond to Trastuzumab, and recently it was not known what causes the resistance to Trastuzumab. It is revealed that patients with ER+/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
s. The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: Erythroblastic Leukemia Viral Oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
and Alzheimer's Disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
In mice loss of signaling by any member of the ErbB family results in embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
nic lethality with defects in organs including the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
. ErbB-1 and ErbB-2 are found in many human cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s, and their excessive signaling may be critical factors in the development and malignancy of these tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s.
Family members
The ErbB protein family consists of 4 members- ErbB-1, also named epidermal growth factor receptorEpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR) - ErbB-2, also named HER2 in humans and neuHER2/neuHER-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...
in rodents - ErbB-3, also named HER3ERBB3Receptor 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....
- ErbB-4, also named HER4
v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain.
Structure
ErbB receptors are made up of an extracellularExtracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
region or ectodomain that contains approximately 620 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, a single transmembrane-spanning region, and a cytoplasmic tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
domain. The extracellular region of each family member is made up of four subdomains, L1, CR1, L2, and CR2, where "L" signifies a leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
-rich repeat domain and "CR" a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
-rich region. These subdomains are shown in blue (L1), green (CR1), yellow (L2), and red (CR2) in the figure below. These subdomains are also referred to as domains I-IV, respectively.
The figure below was created using the pdb
Protein Data Bank (file format)
The Protein Data Bank file format is a textual file format describing the three dimensional structures of molecules held in the Protein Data Bank. The pdb format accordingly provides for description and annotation of protein and nucleic acid structures including atomic coordinates, observed...
files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4).
Kinase activation
The four members of the ErbB protein family are capable of forming homodimersProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, heterodimers
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, and possibly higher-order oligomers upon activation by a subset of potential growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
ligands
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
.
There are 11 growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s that activate ErbB receptors. The ability of each growth factor to activate each of the ErbB receptors is shown in the table below, + and - signifying ability and inability to activate each of the ErbB receptors respectively.
| Ligand Ligand (biochemistry) In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen... |
Receptor Receptor (biochemistry) In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism... |
|||
| ErbB-1 | ErbB-2 | ErbB-3 | ErbB-4 | |
| + | - | - | - | |
| TGF-α TGF alpha Transforming growth factor alpha is upregulated in some human cancers. It is produced in macrophages, brain cells, and keratinocytes, and induces epithelial development. It is closely related to EGF, and can also bind to the EGF receptor with similar effects... |
+ | - | - | - |
| HB-EGF | + | - | - | + |
| amphiregulin Amphiregulin Amphiregulin, also known as AREG, is a protein which in humans is encoded by the AREG gene.- Function:The protein encoded by this gene is a member of the epidermal growth factor family. It is an autocrine growth factor as well as a mitogen for astrocytes, Schwann cells, and fibroblasts... |
+ | - | - | - |
| betacellulin Betacellulin Betacellulin is a protein that in humans is encoded by the BTC gene located on chromosome 4 at locus 4q13-q21. Betacellulin is a member of the EGF family of growth factors. It is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events... |
+ | - | - | + |
| epigen Epigen Epigen is a member of the epidermal growth factor family.... |
+ | - | - | - |
| epiregulin Epiregulin Epiregulin is a protein that in humans is encoded by the EREG gene.- Structure :Epiregulin consists of 46 amino acid residues. Its secondary structure contains approximately 30 percent of β-sheet in the strand. Some of the residues form loops and turns due to the hydrogen bonding... |
+ | - | - | + |
| neuregulin 1 Neuregulin 1 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... |
- | - | + | + |
| neuregulin 2 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... |
- | - | + | + |
| neuregulin 3 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... |
- | - | - | + |
| neuregulin 4 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... |
- | - | - | + |
When not bound to a ligand the extracellular regions of ErbB-1, -3, and -4 are found in a 'tethered' conformation in which a 10-amino-acid-long dimerisation arm is unable to mediate monomer-monomer interactions. In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2, the dimerisation arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible. The consequence of ectodomain dimerisation is the positioning of two cytoplasmic domain such that transphosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of specific 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...
, serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
, and threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
amino acids can occur within the cytoplasmic domain of each ErbB. At least 10 specific tyrosines, 7 serines, and 2 threonines have been identified within the cytoplamic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerisation. Although a number of potential phosphorylation sites exist, upon dimerisation only one or much more rarely two of these sites are phosphorylated at any one time.
Role in cancer
ErbB-1 is overexpressed in many cancers. Drugs such as panitumumabPanitumumab
Panitumumab , formerly ABX-EGF, is a fully human monoclonal antibody specific to the epidermal growth factor receptor ....
, cetuximab
Cetuximab
Cetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...
, gefitinib
Gefitinib
Gefitinib INN , trade name Iressa, is a drug used in the treatment of certain types of cancer, particularly those with mutated and overactive EGFR. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor in target cells...
, erlotinib
Erlotinib
Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
are used to inhibit it. It has recently been shown that acquired resistance to cetuximab and gefitinib can be linked to hyperactivity of ErbB-3.
This is linked to an acquired overexpression of c-MET
C-MET
c-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor . The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity...
, which phosphorylates ErbB-3, which in turn activates the Akt pathway.
ErbB-2 (HER-2) is often overexpressed in breast cancer. The drug Trastuzumab (Herceptin) targets this receptor. Only one-third of the women respond to Trastuzumab, and recently it was not known what causes the resistance to Trastuzumab. It is revealed that patients with ER+/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.