These are transmembrane receptors linked
with intracellular enzymes; physiological receptors consisting of an
extracellular ligand-binding domain and an intracellular effector domain
(intrinsic enzymatic activity) which activates the signal transduction pathway
that leads to amplification and propagation of signals within the cell to alter
cellular process via secondary messenger or transducers.
The receptor molecules consist of single
polypeptide chains with large, cysteine-rich extracellular domains, a short
hydrophobic transmembrane domain (single α-helix), and an intracellular region
containing one or more protein kinase domains.
Signal Transduction Pathway:
1. Ligand Binding
The inactive state of receptors is
monomeric; when activated, these receptors undergo conformational changes
resulting in increased cytosolic enzyme activity. This response lasts from
minutes to an hour.
2. Conformational Change
When the ligand binds to two of its
receptor subunits it induces dimerization of the receptor - cross
phosphorylation of the kinase domains on multiple tyrosine residues.
3. Auto- phosphorylation
Binding of ligand and conformational
changes- their intrinsic tyrosine kinase activity causes auto-phosphorylation
and phosphorylates other peptides or proteins that subsequently activate other
important cellular signals.
4. Kinase Cascade
The activation of a protein kinase cascade;
recruiting enzymes: phosphor-tyrosine-presenting proteins can attract adaptor
molecules, which in turn attract other transducer and leads to their
phosphorylation (transfer of phosphate).
“This cascade of activations results in a multiplication of the initial signal.”
5. Gene Transcription
The secondary messengers amplify and
transduce the hormonal signal by activating the transcription factor
responsible for the transcription. The transcripted mRNA gets translated into
the ribosome and carries out the physiological response.
6. Intercellular signal termination and Desensitization of the receptors
- The phosphorylated substrate proteins are acted upon by kinases and their action are terminated, but not before the signal has been greatly amplified.
- Frequent activation (dimerization) of the receptor promotes receptor internalization and subsequent degradation in the lysosomes.
Types of Enzyme-Linked Receptors:
- Receptor
Tyrosine Kinases
The most abundant type of enzyme-linked
receptor- intracellular region possesses tyrosine kinase activity and causes
kinase cascade of the Ras/ Raf pathway (e.g. ligand-Insulin).
- Serine
/ Threonine kinase Receptors
Protein ligands activate receptors that
have a serine/threonine kinase domain which phosphorylates a gene regulatory
protein and brings about cellular changes.
- JAK-STAT Binding Receptors
These receptors have no intrinsic enzymatic
activity; it follows the JAK-STAT pathway, Janus kinase (JAK) phosphorylates
signal transducers and activators of transcription (STATs), which translocate
to the nucleus and regulate transcription.
- Toll-like
Receptors
The Toll-like receptor domain lacks
intrinsic enzymatic activity; it recruits the interleukin-associated kinases
for transcriptional activation of inflammatory genes.
- TNF-α
Receptors
The mechanism of action of tumor necrosis
factor (TNF-α) signaling starts by timerazitation of the receptors and leads to
subsequent phosphorylation of the transcriptional factors.
- Natriuretic
Peptide Receptors
Natriuretic Peptide Receptors are the
signaling pathways that regulate the synthesis of cyclic GMP in cells: decrease
blood pressure, to reduce cardiac hypertrophy and fibrosis.
Major/ key Signal Transduction Pathway
Clinical Significance
The Enzyme-Linked or Catalytic receptors
are involved in cell survival (e.g. sugar uptake by insulin action),
proliferation, immunity and it also plays an important role in cancer therapy
by the mechanisms of apoptosis. Imatinib, Vemurafenib, Ruxolitinib are just
some of the drugs which act by these receptors.
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Very helpful and informative...
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It is so helpful..
ReplyDeletefurther details on the different types of enzyme-linked receptors will be posted .....
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