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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.
[6]
Specific proteins containing these domains include Src and phospholipase Cγ, the phosphorylation and activation of these two
proteins on receptor binding, leading 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]
[edit] Families
[edit] Epidermal growth factor receptor family
For more details on this topic, see ErbB.
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.
[7]
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.
[8]
[edit] Fibroblast growth factor receptor (FGFR) family
For more details on this topic, see fibroblast growth factor receptor.
Fibroblast growth factors comprise the largest family of growth factor ligands at 23 members.
[9]
The natural alternate splicing of four fibroblast growth factor
receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR.
[10]
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.
[11]
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.
[10]
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.
[12]
[edit] Vascular endothelial growth factor receptor (VEGFR) family
For more details on this topic, see Vascular endothelial growth factor.
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).
[13]
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.
[edit] RET receptor family
For more details on this topic, see RET proto-oncogene.
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.
[14]
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).
[15]
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.
[16]
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.
[17]
[edit] Eph receptor Family
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For more details on this topic, see Eph_receptor.
Ephrin and Eph receptors are the largest subfamily of RTKs.
Cytokine receptor
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Key steps of the JAK-STAT pathway for type 1 and 2 cytokine receptors
Signal transduction. (Cytokine receptor at center left.)
Cytokine receptors are receptors that bind cytokines.
[1]
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable
characteristics, and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and
also because the redundancy and pleiotropy of cytokines are, in fact, a consequence of their homologous receptors, many authorities are now of the opinion that a
classification of cytokine receptors would be more clinically and experimentally useful.
Classification
A classification of cytokine receptors based on their three-dimensional structure has been attempted. (It must be noted that such a classification, though seemingly
cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.)
•
Type I cytokine receptors, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this
chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency
(X-SCID).
•
Type II cytokine receptors, whose members are receptors mainly for interferons.