Receptor tyrosine kinasess are the high-affinity cell surface receptors for
many polypeptide growth factors, cytokines, and hormones. Of the 90
unique tyrosine kinase genes identified in the human genome, 58 encode receptor
tyrosine kinase proteins. Receptor tyrosine kinases have been shown not
only to be key regulators of normal cellular processes but also to have a
critical role in the development and progression of many types of cancer.
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. Nomenclature
Receptor tyrosine kinase in this article is also known as tyrosine receptor
kinase or tyrosine kinase receptor depending on the permutation. However,
Trk receptor is the name in the context of neurobiology.
Receptor tyrosine kinase classes Approximately 20 different RTK classes
have been identified. 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; moreover, ligand binding to the extracellular domain induces
formation of receptor dimers. 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. The
extracellular N terminal region exhibits a variety of conserved elements
including immunoglobulin-like or epidermal growth factor-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. 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.
Kinase activity In biochemistry, a kinase is a type of
enzyme that transfers phosphate groups from high-energy donor molecules, such
as ATP to specific target molecules; 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 an 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. The phosphorylation of specific tyrosine residues within the
activated receptor creates binding sites for Src homology 2 domain- and
phosphotyrosine binding domain-containing proteins. 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. 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 with their RTK receptors is classified
as paracrine signalling. Families
= Epidermal growth factor receptor family =
The ErbB protein family or epidermal growth factor receptor 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. 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.
= Fibroblast growth factor receptor family =
Fibroblast growth factors comprise the largest family of growth factor ligands
at 23 members. The natural alternate splicing of four fibroblast growth
factor receptor genes results in the production of over 48 different isoforms
of FGFR. These isoforms vary in their ligand binding properties and kinase
domains; however, all share a common extracellular region composed of three
immunoglobulin-like domains, and thus belong to the immunoglobulin
superfamily. 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. 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. = Vascular endothelial growth factor
receptor family = Vascular endothelial growth factor 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 and VEGFR-2.
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 and
VEGFR-2. 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.
A third receptor has been discovered; 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. 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 family of extracellular signalling molecules or ligands.
In order to activate RET, first GFLs must form a complex with a
glycosylphosphatidylinositol-anchored co-receptor. The co-receptors themselves
are classified as members of the GDNF receptor-α protein family. Different
members of the GFRα family exhibit a specific binding activity for a specific
GFLs. 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. = Eph receptor family =
Ephrin and Eph receptors are the largest subfamily of RTKs.
= Discoidin domain receptor family = The DDRs are unique RTKs in that they
bind to collagens rather than soluble growth factors.
See also References
External links Tyrosine Kinase Receptors at the US
National Library of Medicine Medical Subject Headings
EC 2.7.10.1