Receptor tyrosine kinase

Last updated
receptor protein-tyrosine kinase
VEGF receptors.png
Identifiers
EC no. 2.7.10.1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
Identifiers
SymbolPkinase_Tyr
Pfam PF07714
OPM superfamily 186
OPM protein 2k1k
Membranome 3
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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] The receptors are generally activated by dimerization and substrate presentation. 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]

Contents

History

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

Classes

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)

Structure

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]

Kinase activity

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.

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.

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.

Families

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 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]

Regulation

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

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

<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">Signal transduction</span> Cascade of intracellular and molecular events for transmission/amplification of signals

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 is catalyzed by protein kinases, ultimately resulting 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 known as a signaling pathway.

<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.

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular 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.

<span class="mw-page-title-main">Platelet-derived growth factor</span> Signaling glycoprotein regulating cell proliferation

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).

<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.

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">Platelet-derived growth factor receptor</span> Cell surface receptors

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.

<span class="mw-page-title-main">VEGF receptor</span> Protein family

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

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.

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

<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">Fibroblast growth factor receptor 4</span> 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.

<span class="mw-page-title-main">FLT4</span> 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.

A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is 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.

<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">Kari Alitalo</span> Finnish MD and a medical researcher

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 US. 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.

<span class="mw-page-title-main">Tyrosine phosphorylation</span> Phosphorylation of peptidyl-tyrosine

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.

References

  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. S2CID   4324726.
  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/j.ceb.2007.02.008. 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. S2CID   23069349.
  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. S2CID   28828504.
  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. doi: 10.1242/jcs.114.5.853 . 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. S2CID   32315320.
  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. S2CID   46427535.
  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. doi:10.1177/117727190700200029. 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.