ErbB

Last updated
EGF receptor family
Identifiers
SymbolErbB
InterPro IPR016245
Membranome 1203

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1 (EGFR, ErbB1), Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). 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, [1] while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. [2]

Contents

ErbB protein family signaling is important for development. For example, ErbB-2 and ErbB-4 knockout mice die at midgestation leads to deficient cardiac function associated with a lack of myocardial ventricular trabeculation and display abnormal development of the peripheral nervous system. [3] In ErbB-3 receptor mutant mice, they have less severe defects in the heart and thus are able to survive longer throughout embryogenesis. [3] Lack of Schwann cell maturation leads to degeneration of motor and sensory neurons. [3] 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 cancers, and their excessive signaling may be critical factors in the development and malignancy of these tumors. [2]

Family members

The ErbB protein family consists of 4 members

v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain.

Structure

All four ErbB receptor family members are nearly same in the structure having single-chain of modular glycoproteins. [4] This structure is made up of an extracellular region or ectodomain or ligand binding region that contains approximately 620 amino acids, a single transmembrane-spanning region containing approximately 23 residues, and an intracellular cytoplasmic tyrosine kinase domain containing up to approximately 540 residues. [4] [5] [6] The extracellular region of each family member is made up of 4 subdomains, L1, CR1, L2, and CR2, where "L" signifies a leucine-rich repeat domain and "CR" a cysteine-rich region, and these CR domains contain disulfide modules in their structure as 8 disulfide modules in CR1 domain, whereas 7 modules in CR2 domain. [4] 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. [5] [7] [8] The intracellular/cytoplasmic region of the ErbB receptor consists mainly of three subdomains: A juxtamembrane with approximately 40 residues, a kinase domain containing approximately 260 residues and a C-terminal domain of 220-350 amino acid residues that become activated via phosphorylation of its tyrosine residues that mediates interactions of other ErbB proteins and downstream signaling molecules. [4] [9]

The figure below shows the tridimensional structure of the ErbB family proteins, using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4): [10] [11] [12] [13]

Comparison of ErbB extracellular domain structures Erb fig.jpeg
Comparison of ErbB extracellular domain structures

ErbB and Kinase activation

The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher-order oligomers upon activation by a subset of potential growth factor ligands. [14] There are 11 growth factors that activate ErbB receptors.

The ability ('+') or inability ('-') of each growth factor to activate each of the ErbB receptors is shown in the table below: [15]

A superposition of similar interfaces observed in crystal structures of the ERBB kinases, including EGFR, ERBB2 (HER2) and ERBB4 (HER4). The protein chains are colored from blue to red from N to C terminus. The kinase at the top of each dimer (as shown) activates the kinase at the bottom of each dimer (Zhang et al., Cell v. 125, pp. 1137-1149, 2008). The cluster was identified with the ProtCID database. The image was made with PyMOL. Activation of ERBB kinases.png
A superposition of similar interfaces observed in crystal structures of the ERBB kinases, including EGFR, ERBB2 (HER2) and ERBB4 (HER4). The protein chains are colored from blue to red from N to C terminus. The kinase at the top of each dimer (as shown) activates the kinase at the bottom of each dimer (Zhang et al., Cell v. 125, pp. 1137–1149, 2008). The cluster was identified with the ProtCID database. The image was made with PyMOL.
Ligand Receptor
ErbB-1ErbB-2ErbB-3ErbB-4
EGF +---
TGF-α +---
HB-EGF +--+
amphiregulin +---
betacellulin +--+
epigen +---
epiregulin +--+
neuregulin 1 --++
neuregulin 2 --++
neuregulin 3 ---+
neuregulin 4 ---+

The dimerization occurs after ligand bind to the extracellular domain of the ErbB monomers and monomer-monomer interaction establishes activating the activation loop in a kinase domain, that activates the further process of transphosphorylation of the specific tyrosine kinases in the kinase domain of ErbB's intracellular part. [16] [5] [17] It is a complex process due to the domain specificity and nature of the members of ErbB family. [18] Notably, the ErbB1 and ErbB4 are the two most studied and intact among the family of ErbB proteins, Which forms functional intracellular tyrosine kinases. [16] ErbB2 has no known binding ligand and absent of an active kinase domain in ErbB3 make this duo preferable to form heterodimers & share each other's active domains to activate transphosphorylation of the tyrosine kinases. [16] [17] [19] [20] The specific tyrosine molecules mainly trans or auto-phosphorylated are at the site Y992, Y1045, Y1068, Y1148, Y1173 in the tail region of the ErbB monomer. [6] For the activation of kinase domain in the ErbB dimer, asymmetric kinase domain dimer of the two monomers is required with the intact asymmetric (N-C lobe) interface at the site of adjoining monomers. [6] Activation of the tyrosine kinase domain leads to the activation of the whole range of downstream signaling pathways like PLCγ, ERK 1/2, p38 MAPK, PI3-K/Akt and more with the cell. [17] [18]

When not bound to a ligand, the extracellular regions of ErbB1, ErbB3, and ErbB4 are found in a tethered conformation in which a 10-amino-acid-long dimerization arm is unable to mediate monomer-monomer interactions. In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2, the dimerization arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible. [21] The consequence of ectodomain dimerization is the positioning of two cytoplasmic domains 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 cytoplasmic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerization. [22] [23] [24] Although a number of potential phosphorylation sites exist, upon dimerization only one or much more rarely two of these sites are phosphorylated at any one time. [22]

Role in cancer

Phosphorylated tyrosine residues act as binding sites for intracellular signal activators such as Ras. The Ras-Raf-MAPK pathway is a major signalling route for the ErbB family, as is the PI3-K/AKT pathway, both of which lead to increased cell proliferation and inhibition of apoptosis. [25]

Genetic Ras mutations are infrequent in breast cancer but Ras may be pathologically activated in breast cancer by overexpression of ErbB receptors. [26] Activation of the receptor tyrosine kinases generates a signaling cascade where the Ras GTPase proteins are activated to a GTP-bound state. [26] The RAS pathway can couple with the mitogen-activated protein kinase pathway or a number of other possible effectors. [26]

The PI3K/Akt pathway is dysregulated in many human tumors because of mutations altering proteins in the pathway. [27] In relation to breast tumors, somatic activating mutations in Akt and the p110α subunit of the PI3K have been detected in 3–5% and 20–25% of primary breast tumors, respectively. [27] Many breast tumors also have lower levels of PTEN, which is a lipid phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate, thereby reversing the action of PI3K. [27]

EGFR has been found to be overexpressed in many cancers such as gliomas and non-small-cell lung carcinoma. [28] Drugs such as panitumumab, cetuximab, gefitinib, erlotinib, afatinib, and lapatinib [29] are used to inhibit it. Cetuximab is a chimeric human: murin immunoglobulin G1 mAb that binds EGFR with high affinity and promotes EGFR internalization. [28] It has recently been shown that acquired resistance to cetuximab and gefitinib can be linked to hyperactivity of ErbB-3. [30] This is linked to an acquired overexpression of c-MET, which phosphorylates ErbB-3, which in turn activates the AKT pathway. [31] Panitumumab is a human mAb with high EGFR affinity that blocks ligand-binding to induce EGFR internalization. [28] Panitumumab efficacy has been tested in a variety of advanced cancer patients, including renal carcinomas and metastatic colorectal cancer in clinical trials. [28]

ErbB2 overexpression can occur in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types. [28] Trastuzumab or Herceptin inhibits downstream signal cascades by selectively binding to the extracellular domain of ErbB-2 receptors to inhibit it. [28] This leads to decreased proliferation of tumor cells. [28] Trastuzumab targets tumor cells and causes apoptosis through the immune system by promoting antibody-dependent cellular cytotoxicity. [28] Two thirds of women respond to trastuzumab. [32] Although herceptin works well in most breast cancer cases, it has not been yet elucidated as to why some HER2-positive breast cancers don't respond well. Research suggests that a low FISH test ratio in estrogen receptor positive breast cancers are less likely to respond to this drug. [33] ErbB expression as also been linked to cutaneous Squamous Cell Carcinoma (cSCC) development, where the over-expression of these receptors has been found in cSCC tumors. Based on a study conducted by Cañueto et al. (2017), ErbB over-expression in tumors was linked to lymph node progression and metastasis stage progression in cSCC. [34]

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

<span class="mw-page-title-main">Gefitinib</span> Drug used in fighting breast, lung, and other cancers

Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

<span class="mw-page-title-main">Epidermal growth factor receptor</span> Transmembrane protein

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) 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. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">Platelet-derived growth factor receptor</span> Protein family

Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.

<span class="mw-page-title-main">TGF alpha</span> Protein

Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to receptors capable of protein kinase activity for cellular signaling.

Matuzumab is a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor (EGFR) with high affinity. The mouse monoclonal antibody (mAb425) from which matuzumab was developed at the Wistar Institute in Philadelphia, Pennsylvania

Zalutumumab is a fully human IgG1 monoclonal antibody (mAb) directed towards the epidermal growth factor receptor (EGFR). It is a product developed by Genmab in Utrecht, the Netherlands. Specifically, zalutumumab is designed for the treatment of squamous cell carcinoma of the head and neck (SCCHN), a type of cancer.

A growth factor receptor is a receptor that binds to a growth factor. Growth factor receptors are the first stop in cells where the signaling cascade for cell differentiation and proliferation begins. Growth factors, which are ligands that bind to the receptor are the initial step to activating the growth factor receptors and tells the cell to grow and/or divide.

<span class="mw-page-title-main">ERBB3</span> Protein found in humans

Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.

<span class="mw-page-title-main">ERBB4</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">STAT5A</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the STAT5A gene. STAT5A orthologs have been identified in several placentals for which complete genome data are available.

<span class="mw-page-title-main">Proto-oncogene tyrosine-protein kinase Src</span> Mammalian protein found in Homo sapiens

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src, is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. It belongs to a family of Src family kinases and is similar to the v-Src gene of Rous sarcoma virus. It includes an SH2 domain, an SH3 domain and a tyrosine kinase domain. Two transcript variants encoding the same protein have been found for this gene.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

<span class="mw-page-title-main">Autophosphorylation</span>

Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.

References

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