Receptor tyrosine kinase

Last updated
receptor protein-tyrosine kinase
VEGF receptors.png
EC number
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Pfam PF07714
OPM superfamily 186
OPM protein 2k1k
Membranome 3

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. [1] 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. [2] Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. [3] 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. [4]

Cell surface receptor

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.

A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

Cytokine broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling

Cytokines are a broad and loose category of small proteins that are important in cell signaling. Cytokines are peptides, and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors, but generally not hormones or growth factors. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.



The first RTKs to be discovered were EGF and NGF in the 1960s, but the classification of receptor tyrosine kinases was not developed until the 1970s. [5]


Approximately 20 different RTK classes have been identified. [6]

  1. RTK class I (EGF receptor family) (ErbB family)
  2. RTK class II (Insulin receptor family)
  3. RTK class III (PDGF receptor family)
  4. RTK class IV (VEGF receptors family)
  5. RTK class V (FGF receptor family)
  6. RTK class VI (CCK receptor family)
  7. RTK class VII (NGF receptor family)
  8. RTK class VIII (HGF receptor family)
  9. RTK class IX (Eph receptor family)
  10. RTK class X (AXL receptor family)
  11. RTK class XI (TIE receptor family)
  12. RTK class XII (RYK receptor family)
  13. RTK class XIII (DDR receptor family)
  14. RTK class XIV (RET receptor family)
  15. RTK class XV (ROS receptor family)
  16. RTK class XVI (LTK receptor family)
  17. RTK class XVII (ROR receptor family)
  18. RTK class XVIII (MuSK receptor family)
  19. RTK class XIX (LMR receptor)
  20. RTK class XX (Undetermined)


Most RTKs are single subunit receptors but some exist as multimeric complexes, e.g., the insulin receptor that forms disulfide linked dimers in the presence of hormone (insulin); moreover, ligand binding to the extracellular domain induces formation of receptor dimers. [7] Each monomer has a single hydrophobic transmembrane-spanning domain composed of 25 to 38 amino acids, an extracellular N terminal region, and an intracellular C terminal region. [8] The extracellular N terminal region exhibits a variety of conserved elements including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, or cysteine-rich regions that are characteristic for each subfamily of RTKs; these domains contain primarily a ligand-binding site, which binds extracellular ligands, e.g., a particular growth factor or hormone. [2] The intracellular C terminal region displays the highest level of conservation and comprises catalytic domains responsible for the kinase activity of these receptors, which catalyses receptor autophosphorylation and tyrosine phosphorylation of RTK substrates. [2]

Protein subunit single protein molecule that assembles with other protein molecules to form a protein complex

In structural biology, a protein subunit is a single protein molecule that assembles with other protein molecules to form a protein complex. Some naturally occurring proteins have a relatively small number of subunits and therefore described as oligomeric, for example hemoglobin or DNA polymerase. Others may consist of a very large number of subunits and therefore described as multimeric, for example microtubules and other cytoskeleton proteins. The subunits of a multimeric protein may be identical, homologous or totally dissimilar and dedicated to disparate tasks.

Insulin receptor protein-coding gene in the species Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of tyrosine kinase receptors. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

A monomer is a molecule that can be reacted together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.

Kinase activity

In biochemistry, a kinase is a type of enzyme that transfers phosphate groups (see below) from high-energy donor molecules, such as ATP (see below) to specific target molecules (substrates); the process is termed phosphorylation . The opposite, an enzyme that removes phosphate groups from targets, is known as a phosphatase. Kinase enzymes that specifically phosphorylate tyrosine amino acids are termed tyrosine kinases.

Biochemistry study of chemical processes in living organisms

Biochemistry, sometimes called biological chemistry, is the study of chemical processes within and relating to living organisms. Biochemical processes give rise to the complexity of life.

Enzyme Large biological molecule that acts as a catalyst

Enzymes are macromolecular biological catalysts that accelerate chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and a new field of pseudoenzyme analysis has recently grown up, recognising that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

Phosphate salt or ester of phosphoric acid

A Phosphate is a chemical derivative of phosphoric acid. The phosphate ion (PO
is an inorganic chemical, the conjugate base that can form many different salts. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Of the various phosphoric acids and phosphates, organic phosphates are important in biochemistry and biogeochemistry, and inorganic phosphates are mined to obtain phosphorus for use in agriculture and industry. At elevated temperatures in the solid state, phosphates can condense to form pyrophosphates.

When a growth factor binds to the extracellular domain of a RTK, its dimerization is triggered with other adjacent RTKs. Dimerization leads to a rapid activation of the protein's cytoplasmic kinase domains, the first substrate for these domains being the receptor itself. The activated receptor as a result then becomes autophosphorylated on multiple specific intracellular tyrosine residues.

Tyrosine Amino acid

Tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Greek tyrós, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA.

Residue (chemistry) in chemistry, whatever remains or acts as a contaminant after a given class of events

In chemistry residue is whatever remains or acts as a contaminant after a given class of events.

Signal transduction

Through diverse means, extracellular ligand binding will typically cause or stabilize receptor dimerization. This allows a tyrosine in the cytoplasmic portion of each receptor monomer to be trans-phosphorylated by its partner receptor, propagating a signal through the plasma membrane. [9] The phosphorylation of specific tyrosine residues within the activated receptor creates binding sites for Src homology 2 (SH2) domain- and phosphotyrosine binding (PTB) domain-containing proteins. [10] [11] Specific proteins containing these domains include Src and phospholipase Cγ. Phosphorylation and activation of these two proteins on receptor binding lead to the initiation of signal transduction pathways. Other proteins that interact with the activated receptor act as adaptor proteins and have no intrinsic enzymatic activity of their own. These adaptor proteins link RTK activation to downstream signal transduction pathways, such as the MAP kinase signalling cascade. [2] An example of a vital signal transduction pathway involves the tyrosine kinase receptor, c-met, which is required for the survival and proliferation of migrating myoblasts during myogenesis. A lack of c-met disrupts secondary myogenesis and—as in LBX1—prevents the formation of limb musculature. This local action of FGFs (Fibroblast Growth Factors) with their RTK receptors is classified as paracrine signalling. As RTK receptors phosphorylate multiple tyrosine residues, they can activate multiple signal transduction pathways.


Epidermal growth factor receptor family

The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease. [12] In mice, loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, 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 cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors. [13]

Fibroblast growth factor receptor (FGFR) family

Fibroblast growth factors comprise the largest family of growth factor ligands at 23 members. [14] The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR. [15] These isoforms vary in their ligand binding properties and kinase domains; however, all share a common extracellular region composed of three immunoglobulin (Ig)-like domains (D1-D3), and thus belong to the immunoglobulin superfamily. [16] Interactions with FGFs occur via FGFR domains D2 and D3. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor. This is not the case with FGF-7, however, which can activate only FGFR2b. [15] A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain, and one isoform, FGFR5γ, only contains the extracellular domains D1 and D2. [17]

Vascular endothelial growth factor receptor (VEGFR) family

Vascular endothelial growth factor (VEGF) is one of the main inducers of endothelial cell proliferation and permeability of blood vessels. Two RTKs bind to VEGF at the cell surface, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). [18]

The VEGF receptors have an extracellular portion consisting of seven Ig-like domains so, like FGFRs, belong to the immunoglobulin superfamily. They also possess a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). A third receptor has been discovered (VEGFR-3); however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D.

RET receptor family

The natural alternate splicing of the RET gene results in the production of 3 different isoforms of the protein RET. RET51, RET43, and RET9 contain 51, 43, and 9 amino acids in their C-terminal tail, respectively. [19] The biological roles of isoforms RET51 and RET9 are the most well studied in-vivo , as these are the most common isoforms in which RET occurs.

RET is the receptor for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules or ligands (GFLs). [20]

In order to activate RET, first GFLs must form a complex with a glycosylphosphatidylinositol (GPI)-anchored co-receptor. The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1-GFRα4) exhibit a specific binding activity for a specific GFLs. [21] Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggering trans-autophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each RET molecule. Phosphorylation of these tyrosines then initiates intracellular signal transduction processes. [22]

Eph receptor family

Ephrin and Eph receptors are the largest subfamily of RTKs.

Discoidin domain receptor (DDR) family

The DDRs are unique RTKs in that they bind to collagens rather than soluble growth factors. [23]


The receptor tyrosine kinase (RTK) pathway is carefully regulated by a variety of positive and negative feedback loops. [24] Because RTKs coordinate a wide variety of cellular functions such as cell proliferation and differentiation, they must be regulated to prevent severe abnormalities in cellular functioning such as cancer and fibrosis. [25]

Protein tyrosine phosphatases

Protein Tyrosine Phosphatase (PTPs) are a group of enzymes that possess a catalytic domain with phosphotyrosine-specific phosphohydrolase activity. PTPs are capable of modifying the activity of receptor tyrosine kinases in both a positive and negative manner. [26] PTPs can dephosphorylate the activated phosphorylated tyrosine residues on the RTKs [27] which virtually leads to termination of the signal. Studies involving PTP1B, a widely known PTP involved in the regulation of the cell cycle and cytokine receptor signaling, has shown to dephosphorylate the epidermal growth factor receptor [28] and the insulin receptor. [29] Some PTPs, on the other hand, are cell surface receptors that play a positive role in cell signaling proliferation. Cd45, a cell surface glycoprotein, plays a critical role in antigen-stimulated dephosphorylation of specific phosphotyrosines that inhibit the Src pathway. [30]


Herstatin is an autoinhibitor of the ErbB family, [31] which binds to RTKs and blocks receptor dimerization and tyrosine phosphorylation. [27] CHO cells transfected with herstatin resulted in reduced receptor oligomerization, clonal growth and receptor tyrosine phosphorylation in response to EGF. [32]

Receptor endocytosis

Activated RTKs can undergo endocytosis resulting in down regulation of the receptor and eventually the signaling cascade. [3] The molecular mechanism involves the engulfing of the RTK by a clathrin-mediated endocytosis, leading to intracellular degradation. [3]

Drug therapy

RTKs have become an attractive target for drug therapy due to their implication in a variety of cellular abnormalities such as cancer, degenerative diseases and cardiovascular diseases. The United States Food and Drug Administration (FDA) has approved several anti-cancer drugs caused by activated RTKs. Drugs have been developed to target the extracellular domain or the catalytic domain, thus inhibiting ligand binding, receptor oligomerization. [33] Herceptin, a monoclonal antibody that is capable of binding to the extracellular domain of RTKs, has been used to treat HER2 overexpression in breast cancer. [34]

Small molecule inhibitors and monoclonal antibodies (approved by the US Food and Drug Administration) against RTKs for cancer therapy [3]
Small MoleculeTargetDiseaseApproval Year
Imatinib (Gleevec)PDGFR, KIT, Abl, ArgCML, GIST2001
Gefitinib (Iressa)EGFREsophageal cancer, Glioma2003
Erlotinib (Tarceva)EGFREsophageal cancer, Glioma2004
Sorafenib (Nexavar)Raf, VEGFR, PDGFR, Flt3, KITRenal cell carcinoma2005
Sunitinib (Sutent)KIT, VEGFR, PDGFR, Flt3Renal cell carcinoma, GIST, Endocrine pancreatic cancer2006
Dasatinib (Sprycel)Abl, Arg, KIT, PDGFR, SrcImatinib-resistant CML2007
Nilotinib (Tasigna)Abl, Arg, KIT, PDGFRImatinib-resistant CML2007
Lapatinib (Tykerb)EGFR, ErbB2Mammary carcinoma2007
Trastuzumab (Herceptin)ErbB2Mammary carcinoma1998
Cetuximab (Erbitux)EGFRColorectal cancer, Head and neck cancer2004
Bevacizumab (Avastin)VEGFLung cancer, Colorectal cancer2004
Panitumumab (Vectibix)EGFRColorectal cancer2006

+ Table adapted from "Cell signalling by receptor-tyrosine kinases," by Lemmon and Schlessinger's, 2010. Cell, 141, p. 1117–1134.

See also

Related Research Articles

Protein kinase enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase enzyme that modifies other molecules, mostly proteins, by chemically adding phosphate groups to them (phosphorylation). 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 518 protein kinase genes and they constitute about 2% of all human genes. 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. Protein kinases are also found in bacteria and plants, and include the pseudokinase sub-family, which exhibit unusual features including atypical nucleotide binding and weak, or no, catalytic activity and are part of a much larger pseudoenzyme group of 'degraded' enzyme relatives that are found throughout life, where they take an active participation in mechanistic cellular signaling.

Signal transduction cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events as a signaling pathway.

Tyrosine kinase class of enzymes

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. Tyrosine kinases are a subclass of protein kinase.

Paracrine signaling

Paracrine signaling is a form of cell signaling or cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

Platelet-derived growth factor

Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).

Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF), is a signal protein produced by cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

Epidermal growth factor receptor protein-coding gene in the species Homo sapiens

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.

Platelet-derived growth factor receptor

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.

The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the fibroblast growth factor (FGF) family of proteins. Some of these receptors are involved in pathological conditions. For example, a point mutation in FGFR3 can lead to achondroplasia.

VEGF receptor

VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing.

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, Her2, 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, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

ERBB3 protein-coding gene in the species Homo sapiens

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

ERBB4 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.

Fibroblast growth factor receptor 4 protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the FGFR4 gene. FGFR4 has also been designated as CD334.

FLT4 protein-coding gene in the species Homo sapiens

Fms-related tyrosine kinase 4, also known as FLT4, is a protein which in humans is encoded by the FLT4 gene.

Non-receptor tyrosine kinases (nRTKs) are cytosolic enzymes that are responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.

Kari Alitalo Finnish research professor (Academy of Finland), director of Translational Cancer Biology research program (AlitaloLab, Institute of Biomedicine, University of Helsinki) and director of Wihuri Research Institute (Helsinki)

Kari Kustaa Alitalo is a Finnish MD and a medical researcher. He is a foreign associated member of the National Academy of Sciences of the USA. He became famous for his discoveries of several receptor tyrosine kinases (RTKs) and the first growth factor capable of inducing lymphangiogenesis: vascular endothelial growth factor C (VEGF-C). In the years 1996–2007 he was Europe's second most cited author in the field of cell biology. Alitalo is currently serving as an Academy Professor for the Academy of Finland.

Autophosphorylation The phosphorylation by a protein of one or more of its own amino acid residues (cis-autophosphorylation), or residues on an identical protein (trans-autophosphorylation).

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.

Tyrosine phosphorylation

Tyrosine phosphorylation is the addition of a phosphate (PO43−) group to the amino acid tyrosine on a protein. It is one of the main types of protein phosphorylation. This transfer is made possible through enzymes called tyrosine kinases. Tyrosine phosphorylation is a key step in signal transduction and the regulation of enzymatic activity.


  1. Robinson DR, Wu YM, Lin SF (November 2000). "The protein tyrosine kinase family of the human genome". Oncogene. 19 (49): 5548–57. doi:10.1038/sj.onc.1203957. PMID   11114734.
  2. 1 2 3 4 Zwick E, Bange J, Ullrich A (September 2001). "Receptor tyrosine kinase signalling as a target for cancer intervention strategies". Endocrine-Related Cancer. 8 (3): 161–73. doi:10.1677/erc.0.0080161. PMID   11566607.
  3. 1 2 3 4 Lemmon MA, Schlessinger J (June 2010). "Cell signaling by receptor tyrosine kinases". Cell. 141 (7): 1117–34. doi:10.1016/j.cell.2010.06.011. PMC   2914105 . PMID   20602996.
  4. Hubbard SR, Till JH (2000). "Protein tyrosine kinase structure and function". Annual Review of Biochemistry. 69: 373–98. doi:10.1146/annurev.biochem.69.1.373. PMID   10966463.
  5. Schlessinger, J. (3 March 2014). "Receptor Tyrosine Kinases: Legacy of the First Two Decades". Cold Spring Harbor Perspectives in Biology. 6 (3): a008912. doi:10.1101/cshperspect.a008912. PMC   3949355 . PMID   24591517.
  6. Ségaliny, Aude I.; Tellez-Gabriel, Marta; Heymann, Marie-Françoise; Heymann, Dominique (2015). "Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers". Journal of Bone Oncology. 4 (1): 1–12. doi:10.1016/j.jbo.2015.01.001. PMC   4620971 . PMID   26579483.
  7. Lodish; et al. (2003). Molecular cell biology (5th ed.).
  8. Hubbard SR (1999). "Structural analysis of receptor tyrosine kinases". Progress in Biophysics and Molecular Biology. 71 (3–4): 343–58. doi:10.1016/S0079-6107(98)00047-9. PMID   10354703.
  9. Lemmon MA, Schlessinger J (June 2010). "Cell signaling by receptor tyrosine kinases". Cell. 141 (7): 1117–34. doi:10.1016/j.cell.2010.06.011. PMC   2914105 . PMID   20602996.
  10. Pawson T (February 1995). "Protein modules and signalling networks". Nature. 373 (6515): 573–80. Bibcode:1995Natur.373..573P. doi:10.1038/373573a0. PMID   7531822.
  11. Ren S, Yang G, He Y, Wang Y, Li Y, Chen Z (October 2008). "The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains". BMC Genomics. 9: 452. doi:10.1186/1471-2164-9-452. PMC   2576256 . PMID   18828911.
  12. Bublil EM, Yarden Y (April 2007). "The EGF receptor family: spearheading a merger of signaling and therapeutics". Current Opinion in Cell Biology. 19 (2): 124–34. doi:10.1016/ PMID   17314037.
  13. Cho HS, Leahy DJ (August 2002). "Structure of the extracellular region of HER3 reveals an interdomain tether". Science. 297 (5585): 1330–3. Bibcode:2002Sci...297.1330C. doi:10.1126/science.1074611. PMID   12154198.
  14. Ornitz DM, Itoh N (2001). "Fibroblast growth factors". Genome Biology. 2 (3): REVIEWS3005. doi:10.1186/gb-2001-2-3-reviews3005. PMC   138918 . PMID   11276432.
  15. 1 2 Duchesne L, Tissot B, Rudd TR, Dell A, Fernig DG (September 2006). "N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding". The Journal of Biological Chemistry. 281 (37): 27178–89. doi:10.1074/jbc.M601248200. PMID   16829530.
  16. Coutts JC, Gallagher JT (December 1995). "Receptors for fibroblast growth factors". Immunology and Cell Biology. 73 (6): 584–9. doi:10.1038/icb.1995.92. PMID   8713482.
  17. Sleeman M, Fraser J, McDonald M, Yuan S, White D, Grandison P, Kumble K, Watson JD, Murison JG (June 2001). "Identification of a new fibroblast growth factor receptor, FGFR5". Gene. 271 (2): 171–82. doi:10.1016/S0378-1119(01)00518-2. PMID   11418238.
  18. Robinson CJ, Stringer SE (March 2001). "The splice variants of vascular endothelial growth factor (VEGF) and their receptors". Journal of Cell Science. 114 (Pt 5): 853–65. PMID   11181169.
  19. Myers SM, Eng C, Ponder BA, Mulligan LM (November 1995). "Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET". Oncogene. 11 (10): 2039–45. PMID   7478523.
  20. Baloh RH, Enomoto H, Johnson EM, Milbrandt J (February 2000). "The GDNF family ligands and receptors - implications for neural development". Current Opinion in Neurobiology. 10 (1): 103–10. doi:10.1016/S0959-4388(99)00048-3. PMID   10679429.
  21. Airaksinen MS, Titievsky A, Saarma M (May 1999). "GDNF family neurotrophic factor signaling: four masters, one servant?". Molecular and Cellular Neurosciences. 13 (5): 313–25. doi:10.1006/mcne.1999.0754. PMID   10356294.
  22. Arighi E, Borrello MG, Sariola H (2005). "RET tyrosine kinase signaling in development and cancer". Cytokine & Growth Factor Reviews. 16 (4–5): 441–67. doi:10.1016/j.cytogfr.2005.05.010. PMID   15982921.
  23. Fu HL, Valiathan RR, Arkwright R, Sohail A, Mihai C, Kumarasiri M, Mahasenan KV, Mobashery S, Huang P, Agarwal G, Fridman R (March 2013). "Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling". The Journal of Biological Chemistry. 288 (11): 7430–7. doi:10.1074/jbc.R112.444158. PMC   3597784 . PMID   23335507.
  24. Ostman A, Böhmer FD (June 2001). "Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases". Trends in Cell Biology. 11 (6): 258–66. doi:10.1016/s0962-8924(01)01990-0. PMID   11356362.
  25. Haj FG, Markova B, Klaman LD, Bohmer FD, Neel BG (January 2003). "Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B". The Journal of Biological Chemistry. 278 (2): 739–44. doi:10.1074/jbc.M210194200. PMID   12424235.
  26. Volinsky N, Kholodenko BN (August 2013). "Complexity of receptor tyrosine kinase signal processing". Cold Spring Harbor Perspectives in Biology. 5 (8): a009043. doi:10.1101/cshperspect.a009043. PMC   3721286 . PMID   23906711.
  27. 1 2 Ledda F, Paratcha G (February 2007). "Negative Regulation of Receptor Tyrosine Kinase (RTK) Signaling: A Developing Field". Biomarker Insights. 2: 45–58. PMC   2717834 . PMID   19662191.
  28. Flint AJ, Tiganis T, Barford D, Tonks NK (March 1997). "Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases". Proceedings of the National Academy of Sciences of the United States of America. 94 (5): 1680–5. Bibcode:1997PNAS...94.1680F. doi:10.1073/pnas.94.5.1680. PMC   19976 . PMID   9050838.
  29. Kenner KA, Anyanwu E, Olefsky JM, Kusari J (August 1996). "Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling". The Journal of Biological Chemistry. 271 (33): 19810–6. doi:10.1074/jbc.271.33.19810. PMID   8702689.
  30. Hermiston ML, Zikherman J, Zhu JW (March 2009). "CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells". Immunological Reviews. 228 (1): 288–311. doi:10.1111/j.1600-065X.2008.00752.x. PMC   2739744 . PMID   19290935.
  31. Justman QA, Clinton GM (2002). "Herstatin, an autoinhibitor of the human epidermal growth factor receptor 2 tyrosine kinase, modulates epidermal growth factor signaling pathways resulting in growth arrest". The Journal of Biological Chemistry. 277 (23): 20618–24. doi:10.1074/jbc.M111359200. PMID   11934884.
  32. Azios NG, Romero FJ, Denton MC, Doherty JK, Clinton GM (August 2001). "Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor". Oncogene. 20 (37): 5199–209. doi:10.1038/sj.onc.1204555. PMID   11526509.
  33. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK (January 2012). "Targeting the EGFR signaling pathway in cancer therapy". Expert Opinion on Therapeutic Targets. 16 (1): 15–31. doi:10.1517/14728222.2011.648617. PMC   3291787 . PMID   22239438.
  34. Carlsson J, Nordgren H, Sjöström J, Wester K, Villman K, Bengtsson NO, Ostenstad B, Lundqvist H, Blomqvist C (June 2004). "HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review". British Journal of Cancer. 90 (12): 2344–8. doi:10.1038/sj.bjc.6601881. PMC   2409528 . PMID   15150568.