Epidermal growth factor receptor
Encyclopedia
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface
receptor
for members of the epidermal growth factor
family (EGF-family) of extracellular
protein ligands
. The epidermal growth factor receptor is a member of the ErbB
family of receptors, a subfamily of four closely related receptor tyrosine kinase
s: EGFR (ErbB-1), HER2/c-neu
(ErbB-2), Her 3
(ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer
. Epidermal Growth Factor was discovered by Stanley Cohen of Vanderbilt University
along with Rita Levi-Montalcini
for which both received the Nobel prize in Physiology or Medicine
in 1986.
s, including epidermal growth factor
and transforming growth factor α
(TGFα) (note, a full list of the ligands able to activate EGFR and other members of the ErbB family is given in the ErbB article). ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon heterodimerization with other family members such as EGFR.
Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer - although there is some evidence that preformed inactive dimers may also exist before ligand binding. In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer. There is also evidence to suggest that clusters of activated EGFRs form, although it remains unclear whether this clustering is important for activation itself or occurs subsequent to activation of individual dimers.
EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine
(Y) residues in the C-terminal domain of EGFR occurs. These include Y992, Y1045, Y1068, Y1148 and Y1173 as shown in the diagram to the left. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domain
s. These downstream signaling proteins initiate several signal transduction
cascades, principally the MAPK
, Akt
and JNK pathways, leading to DNA synthesis
and cell proliferation. Such proteins modulate phenotypes such as cell migration
, adhesion
, and proliferation
. Activation of the receptor is important for the innate immune response in human skin. The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with, and can itself be activated in that manner.
s that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancer
s, including lung cancer
, anal cancer
s and glioblastoma multiforme
. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often observed. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.
Mutations involving EGFR could lead to its constant activation, which could result in uncontrolled cell division – a predisposition for cancer
. Consequently, mutations of EGFR have been identified in several types of cancer, and it is the target of an expanding class of anticancer therapies.
The identification of EGFR as an oncogene
has led to the development of anticancer therapeutics directed against EGFR, including gefitinib
and erlotinib
for lung cancer, and cetuximab
for colon cancer.
Many therapeutic approaches are aimed at the EGFR. Cetuximab and panitumumab
are examples of monoclonal antibody
inhibitors
. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody-dependent cellular cytotoxicity
can be quite different. Other monoclonals in clinical development are zalutumumab
, nimotuzumab
, and matuzumab
. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase.
Another method is using small molecules to inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished.
Gefitinib
, erlotinib
, and lapatinib
(mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase
inhibitors.
There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.
However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene. However, as of 2010 there was no consensus of an accepted approach to combat resistance nor FDA approval of a specific combination. Preclinical results have been reported for AP26113
which targets the T790M mutation.
also activates EGFR, thereby inhibiting regeneration of axons.
(PCI), which contains a small cysteine
-rich module
, called a T-knot scaffold, that is shared by several different protein families, including the EGF family. Structural similarities with these factors can explain the antagonistic effect of PCI.
with:
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
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...
for members of the epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
family (EGF-family) of extracellular
Extracellular
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...
protein 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...
. The epidermal growth factor receptor is a member of the ErbB
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...
family of receptors, a subfamily of four closely related receptor tyrosine kinase
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: EGFR (ErbB-1), HER2/c-neu
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...
(ErbB-2), Her 3
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....
(ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in 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...
. Epidermal Growth Factor was discovered by Stanley Cohen of Vanderbilt University
Vanderbilt University
Vanderbilt University is a private research university located in Nashville, Tennessee, United States. Founded in 1873, the university is named for shipping and rail magnate "Commodore" Cornelius Vanderbilt, who provided Vanderbilt its initial $1 million endowment despite having never been to the...
along with Rita Levi-Montalcini
Rita Levi-Montalcini
Rita Levi-Montalcini , Knight Grand Cross is an Italian neurologist who, together with colleague Stanley Cohen, received the 1986 Nobel Prize in Physiology or Medicine for their discovery of nerve growth factor...
for which both received the Nobel prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 1986.
Function
EGFR (epidermal growth factor receptor) exists on the cell surface and is activated by binding of its specific ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s, including epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
and transforming growth factor 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...
(TGFα) (note, a full list of the ligands able to activate EGFR and other members of the ErbB family is given in the ErbB article). ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon heterodimerization with other family members such as EGFR.
Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer - although there is some evidence that preformed inactive dimers may also exist before ligand binding. In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer. There is also evidence to suggest that clusters of activated EGFRs form, although it remains unclear whether this clustering is important for activation itself or occurs subsequent to activation of individual dimers.
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...
(Y) residues in the C-terminal domain of EGFR occurs. These include Y992, Y1045, Y1068, Y1148 and Y1173 as shown in the diagram to the left. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
s. These downstream signaling proteins initiate several signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
cascades, principally the MAPK
MAPK/ERK pathway
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. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
, Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
and JNK pathways, leading to DNA synthesis
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and cell proliferation. Such proteins modulate phenotypes such as cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, adhesion
Adhesion
Adhesion is any attraction process between dissimilar molecular species that can potentially bring them in close contact. By contrast, cohesion takes place between similar molecules....
, and proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
. Activation of the receptor is important for the innate immune response in human skin. The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with, and can itself be activated in that manner.
Clinical applications
MutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of 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, including lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, anal cancer
Anal cancer
Anal cancer is a type of cancer which arises from the anus, the distal orifice of the gastrointestinal tract. It is a distinct entity from the more common colorectal cancer. The etiology, risk factors, clinical progression, staging, and treatment are all different. Anal cancer is typically a...
s and glioblastoma multiforme
Glioblastoma multiforme
Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...
. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often observed. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.
Mutations involving EGFR could lead to its constant activation, which could result in uncontrolled cell division – a predisposition for 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...
. Consequently, mutations of EGFR have been identified in several types of cancer, and it is the target of an expanding class of anticancer therapies.
The identification of EGFR as an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
has led to the development of anticancer therapeutics directed against EGFR, including 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...
and 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...
for lung cancer, and 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...
for colon cancer.
Many therapeutic approaches are aimed at the EGFR. Cetuximab and panitumumab
Panitumumab
Panitumumab , formerly ABX-EGF, is a fully human monoclonal antibody specific to the epidermal growth factor receptor ....
are examples of monoclonal antibody
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
inhibitors
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody-dependent cellular cytotoxicity
Antibody-dependent cellular cytotoxicity
Antibody-Dependent Cell-Mediated Cytotoxicity is a mechanism of cell-mediated immunity whereby an effector cell of the immune system actively lyses a target cell that has been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune...
can be quite different. Other monoclonals in clinical development are zalutumumab
Zalutumumab
Zalutumumab is a fully human IgG1 monoclonal antibody directed towards the epidermal growth factor receptor . 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 , a type of cancer...
, nimotuzumab
Nimotuzumab
Nimotuzumab is a humanized monoclonal antibody used to treat squamous cell carcinomas of the head and neck, recurrent or refractory high grade malignant glioma, anaplastic astrocytomas, glioblastomas and diffuse...
, and matuzumab
Matuzumab
Matuzumab was a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor with high affinity....
. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase.
Another method is using small molecules to inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished.
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...
, and lapatinib
Lapatinib
Lapatinib , used in the form of lapatinib ditosylate, is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway. It is used in combination therapy for HER2-positive breast cancer...
(mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
inhibitors.
There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.
EGFR and Lung Cancer
New drugs such as IRESSA and Tarceva directly target the EGFR. Patients have been divided into EGFR-positive and EGFR-negative, based upon whether a tissue test shows a mutation. EGFR-positive patients have shown an impressive 60% response rate, which exceeds the response rate for conventional chemotherapy.However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene. However, as of 2010 there was no consensus of an accepted approach to combat resistance nor FDA approval of a specific combination. Preclinical results have been reported for AP26113
AP26113
AP26113 is a small-molecule targeted cancer therapy, developed by ARIAD Pharmaceuticals, Inc. AP26113 has exhibited activity as a potent dual inhibitor of anaplastic lymphoma kinase and epidermal growth factor receptor...
which targets the T790M mutation.
Preclinical
Efficient conversion of strongly absorbed light by plasmonic gold nanoparticles to heat energy and their easy bioconjugation suggest their use as selective photothermal agents in molecular cancer cell targeting. Two oral squamous carcinoma cell lines (HSC 313 and HOC 3 Clone 8) and one benign epithelial cell line (HaCaT) were incubated with anti-epithelial growth factor receptor (EGFR) antibody conjugated gold nanoparticles and then exposed to continuous visible argon ion laser at 514 nm. It is found that the malignant cells require less than half the laser energy to be killed than the benign cells after incubation with anti-EGFR antibody conjugated Au nanoparticles. No photothermal destruction is observed for all types of cells in the absence of nanoparticles at four times energy required to kill the malignant cells with anti-EGFR/Au conjugates bonded. Au nanoparticles thus offer a novel class of selective photothermal agents using a CW laser at low powers.Possible involvement in axonal regeneration
In 2005 it was shown that inhibitors of EGFR could enhance axonal regeneration on non-conducive substrates such as CNS myelin. In July 2007 it was discovered that the blood clotting protein fibrinogenFibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
also activates EGFR, thereby inhibiting regeneration of axons.
Natural EGFR inhibitors
Natural inhibitors include potato carboxypeptidase inhibitorPotato carboxypeptidase inhibitor
Potato carboxypeptidase inhibitor is a naturally occurring protease inhibitor peptide in potatoes that can form complexes with several metallo-carboxypeptidases, inhibiting them in a strong competitive way with a Ki in the nanomolar range...
(PCI), which contains a small 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 module
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
, called a T-knot scaffold, that is shared by several different protein families, including the EGF family. Structural similarities with these factors can explain the antagonistic effect of PCI.
Interactions
Epidermal growth factor receptor 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:
- Androgen receptorAndrogen receptorThe androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
, - ARF4ARF4ADP-ribosylation factor 4 is a protein that in humans is encoded by the ARF4 gene.-Interactions:ARF4 has been shown to interact with Epidermal growth factor receptor.-Further reading:...
, - Beta-cateninBeta-cateninBeta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
, - Caveolin 1,
- Caveolin 3Caveolin 3Caveolin-3 is a protein that in humans is encoded by the CAV3 gene.-Interactions:Caveolin 3 has been shown to interact with Epidermal growth factor receptor, Dysferlin and Dystroglycan.-Further reading:...
, - Cbl geneCbl geneCbl is a mammalian gene encoding several proteins including E3 ubiquitin-protein ligase CBL involved in cell signalling and protein ubiquitination...
, - CBLBCBLBE3 ubiquitin-protein ligase CBL-B is an enzyme that in humans is encoded by the CBLB gene.-Interactions:CBLB has been shown to interact with Epidermal growth factor receptor, Grb2, PIK3R1, SH3KBP1, CRKL and NEDD4.-Further reading:...
, - CBLCCBLCSignal transduction protein CBL-C is a protein that in humans is encoded by the CBLC gene.-Interactions:CBLC has been shown to interact with FYN and Epidermal growth factor receptor.-Further reading:...
, - CDC25ACDC25ACell division cycle 25 homolog A , also known as CDC25A, is a mammalian gene.-Interactions:CDC25A has been shown to interact with ASK1, Epidermal growth factor receptor, C-Raf, CHEK1, Cyclin E1, PIM1 and YWHAB.-Further reading:...
, - CRKCRK (gene)Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
, - DecorinDecorinDecorin is a proteoglycan on average 90 - 140 kilodaltons in size.It belongs to the small leucine-rich proteoglycan family and consists of a protein core containing leucine repeats with a glycosaminoglycan chain consisting of either chondroitin sulfate or dermatan sulfate .Decorin is a small...
, - Epidermal growth factorEpidermal growth factorEpidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
, - GRB14GRB14Growth factor receptor-bound protein 14 is a protein that in humans is encoded by the GRB14 gene.-Interactions:GRB14 has been shown to interact with Epidermal growth factor receptor, Fibroblast growth factor receptor 1 and TNKS2.-Further reading:...
, - Grb2Grb2Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, - Janus kinase 2Janus kinase 2Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
, - MUC1MUC1Mucin 1, cell surface associated or polymorphic epithelial mucin is a mucin encoded by the MUC1 gene in humans. MUC1 is a proteoglycan with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and...
, - NCK1NCK1Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.-Interactions:NCK1 has been shown to interact with DNM1, EIF2B2, KHDRBS1, Lymphocyte cytosolic protein 2, EPH receptor B1, SOCS7, MINK1, MAP4K1, MAP4K4, Abl gene, WIPF1, RRAS, Wiskott-Aldrich syndrome protein,...
, - NCK2NCK2Cytoplasmic protein NCK2 is a protein that in humans is encoded by the NCK2 gene.-Interactions:NCK2 has been shown to interact with LIMS1, Epidermal growth factor receptor, PDGFRB, PTK2, T-cell surface glycoprotein CD3 epsilon chain and TrkB....
- PKC alphaPKC alphaProtein kinase C alpha , also known as PRKCA, refers to both a human gene and the protein that is encoded by it.-Background:...
, - PLCG1PLCG1Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.-Function:The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate...
, - PLSCR1PLSCR1Phospholipid scramblase 1 is an enzyme that in humans is encoded by the PLSCR1 gene.-Interactions:PLSCR1 has been shown to interact with NEU4, SLPI, SHC1, CPSF6, Epidermal growth factor receptor and TFG.-Further reading:...
, - PTPN1PTPN1Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B is an enzyme that is the founding member of the protein tyrosine phosphatase family. In humans it is encoded by the PTPN1 gene...
, - PTPN11PTPN11Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
, - PTPN6PTPN6Tyrosine-protein phosphatase non-receptor type 6 is an enzyme that in humans is encoded by the PTPN6 gene.Also known as Src homology region 2 domain-containing phosphatase-1 .-Interactions:...
, - SH2D3ASH2D3ASH2 domain-containing protein 3A is a protein that in humans is encoded by the SH2D3A gene.-Interactions:SH2D3A has been shown to interact with Epidermal growth factor receptor.-Further reading:...
, - SH3KBP1SH3KBP1SH3 domain-containing kinase-binding protein 1 is an enzyme that in humans is encoded by the SH3KBP1 gene.-Interactions:SH3KBP1 has been shown to interact with B-cell linker, Grb2, SH3GLB2, SH3GL3, SH3GL2, BCAR1, Epidermal growth factor receptor, CBLB, Cbl gene, SOS1, CRK and PAK2.-Further reading:...
, - SHC1SHC1SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
, - SOS1SOS1Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes...
, - SrcSrc (gene)Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
, - STAT1STAT1STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...
, - STAT3STAT3Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
, - STAT5ASTAT5ASignal 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.-Interactions:...
, - Ubiquitin CUbiquitin CUbiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
, and - Wiskott-Aldrich syndrome proteinWiskott-Aldrich syndrome proteinThe Wiskott–Aldrich Syndrome Protein is a 502-amino acid protein that is expressed in cells of the hematopoietic system. In the inactive state, WASp exists in an auto-inhibited conformation with sequences near its C-terminus binding to a region near its N-terminus...
.