ENZYME-ASSOCIATED RECEPTORS

(Insulin Receptor)

Enzyme-associated receptors, also

known as catalytic receptors and kinase-
linked receptors, are integral membrane
proteins which possess both enzymatic
and receptor functions.
The binding of a ligand on its
extracellular side causes enzymatic activity
on its intracellular side. They are
responsible in mediating actions of protein
mediators including growth factors,
cytokines, and hormones such as insulin.
The structure of the receptors of this
type consists of three main parts: the
ligand-binding domain, the transmembrane Figure 1. General structure of enzyme-associated
domain, and the catalytic domain. receptors consisting of the extracellular ligand-
The ligand-binding domain is binding domain, transmembrane domain, and the
cytosolic catalytic domain.
located in the extracellular side and is
responsible for binding specific ligands
which evoke particular cellular responses.
The transmembrane domain spans the membrane and is composed of anα-
helix structure which contains series of hydrophobic amino acids. The
transmembrane domain connects the ligand-binding domain to the catalytic domain
located on the cytosolic side.
The catalytic domain may either have an intrinsic enzyme activity or may
associate directly and activate an enzyme. Enzyme-associated receptors which
have intrinsic enzyme activity are classified into two main types: the receptor tyrosine
kinases (RTKs) and the serine/threonine kinases. Receptors which do not have an
intrinsic enzyme activity but instead associate with an enzyme is classified into the
third type of associated receptors called the cytokine receptors. Figure 1 shows the
basic structure of enzyme-associated receptors.

Receptor tyrosine kinases(RTKs)

Receptor tyrosine kinases are called such because they incorporate a tyrosine
kinase moiety in their intracellular region. They include receptors for growth factors
and other locally released proteins. They also play important roles in regulation of
cell growth, differentiation, and survival.

• RTK Activation
➢ The first
step in the
activation
of RTKs is
the
binding of
a ligand to
a receptor

Figure 2. The process of activation of RTKs through dimerization.

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 which brings two monomers to form a dimer.
➢ The formation of a dimer allows the two kinase residues to phosphorylate
each other which completes the activation of the domain.
➢ The phosphorylated tyrosine residues then serve as docking sites for
intracellular signal transduction/adapter proteins such as the SH2 domain
proteins.
➢ SH2(Src Homology 2) domains possess a highly conserved sequence of
about 100 amino acids. This conserved sequence serves as a recognition
site which enables proteins containing SH2 domains to dock to
phosphorylated tyrosine residues.
➢ Figure 2 summarizes the process of activation of the RTKs.This process of
recognition and subsequent docking constitutes the fundamental event of
signal transduction.

• Growth factor (RAS/RAF/MAP kinase) pathway

One well-characterized pathway which utilizes RTKs is the Growth factor
(RAS/RAF/MAP kinase) pathway. The first step in the pathway is the activation of
the RTKs as discussed above. Once the domain is activated, it binds and
activates the Grb2(Growth factor receptor-bound protein 2). The Grb2 protein
then activates the Ras protein by catalyzing its exchange of GDP with GTP. The
Ras protein in turn activates Raf, which phosphorylates Mek, and which in turn
phosphorylates MAP(mitogen-activated protein) kinase. MAP kinase then
activates transcription factors which initiate gene expression that results in a
variety of cellular responses such as cell division. Figure 3 summarizes the
growth factor (RAS/RAF/MAP kinase) pathway. This pathway forms part of many
intracellular signaling pathways involved in a wide variety of diseases. Mutations
in the genes which code for the proteins in this cascade result to the activation of
the pathway even in the absence of a signal.

Figure 3. The growth factor (RAS/RAF/MAP kinase) pathway.

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• Insulin receptor

Organs of distribution, receptor structure, and receptor sites

One notable receptor classified under RTKs is the insulin receptor. Insulin
receptors are found on the membranes of most tissues, primarily in liver, muscle,
and adipose tissue.Its structure consists of covalently linked heterodimers, each
consisting of an α subunit which serves as the recognition site, and a β subunit
which contains a tyrosine kinase moiety. Figure 4 shows the general structure of
an insulin receptor.

Figure 4. The structure of an insulin receptor consisting of covalently linked

heterodimers.

Endogenous ligands
The insulin receptor is activated by insulin, its endogenous ligands being
IGF(insulin growth factor)-I and IGF-II. Insulin is an anabolic hormone produced
by β cells of the pancreas which promotes the absorption of glucose from the
blood which is then converted into glycogen and/or fats. Its counterpart,
glucagon, is a catabolic hormone produced by the α cells of the pancreas which
raises the concentration of glucose in the blood by converting stored glycogen
into glucose.

Process of signal transduction

After an insulin binds to its receptor, a number of events occur which
ultimately results to a decrease in blood glucose. Figure 5 shows the events
subsequent to the binding of insulin to an insulin receptor which then leads to the
uptake of glucose. As can be seen in the diagram, the binding of the insulin to its
receptor activates the tyrosine kinase domain, which can either bind an IRS
(insulin receptor substrate) or a Ras complex. When an IRS is bound, IRS
becomes activated and in turnactivates phosphoinositol 3 kinase(PI3K), an
enzyme which converts phosphatidylinositol 4,5-bisphosphate(PIP2) into
phosphatidylinositol 3,4,5-triphosphate(PIP3). PIP3 in turn activates protein
kinase B (PKB), which in turn facilitates fusion of endosomes containing glucose
transporter 4 (Glut4) in the plasma membrane. On the other hand, if a Ras

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 complex is bound, Ras becomes activatedwhich then initiates a phosphorylation
cascade resulting into activation of MAP kinase. Activation of MAP kinase then
activates nuclear transcription factors leading to expression of genes involved in
cell growth and metabolism. Once the insulin-insulin receptor complex completes
its function, the receptor is recycled and released back to the surface while the
insulin may either be recycled or degraded by endocytosis.

Figure 5. A diagram showing the events subsequent to the binding of insulin to an

insulin receptor.
Physiologic functions
Insulin serves several physiological functions. It facilitates the entry of glucose
into muscle, adipose, and several other tissues and stimulates the liver to store
glucose in the form of glycogen. It promotes the synthesis of fatty acids in the liver
while inhibiting its breakdown in the adipose tissue. It also stimulates the uptake of
amino acids and increases the permeability of ions such as potassium, magnesium
and phosphate ions.
Pharmacologic Application

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 Diabetes mellitus is a chronic metabolic disorder characterized by a high blood
glucose concentration. It is classified into two types: Type 1 which is known as
insulin dependent diabetes, and Type 2 known as non-insulin dependent diabetes.
Type 1 diabetes is the absolute deficiency of insulin due to the failure of the pancreas
to produce enough of it. Without insulin treatment, diabetic ketoacidosis results
which may result to the death of the patient. Ketoacidosis occurs when the body
uses fats as its primary source of fuel in the absence of glucose. The use of fatty
acids results to a build-up of ketones which is toxic to the body. On the other hand,
type 2 diabetes results from insulin resistance where the cells fail to respond to
insulin. As the disease progresses, insulin secretion is also impaired.
Treatment of diabetes is done with the use of insulin and other hypoglycemic
drugs. Insulin includes the human insulin, intermediate acting insulin (isophane), and
long-acting insulin (zinc suspension). The use of insulin usually results to
hypoglycemia, to lessen this undesired effect, designer insulin (lispro and gargline)
which alters insulin kinetics were made. Other oral hypoglycemic drugs include
biguanides(metformin), sulfonylureas(tolbutamide, glibenclamide, nateglinide),
thazolidinediones(pioglitazone), gliptins(sitagliptin), and α-glucosidase inhibitors
(acarbose).
Serine/threonine kinase receptors

Serine/threonine kinases are similar in structure to RTKs but phosphorylate

serine and/or threonine residues instead of tyrosine. They play a role in cell
proliferation, programmed cell death, cell differentiation, and embryonic
development. One receptor of this type is the receptor for transforming growth
factor (TGF).

Cytokine receptors

Cytokine receptors, also known as tyrosine-kinase associated receptors, lack

intrinsic enzyme activity. Each cytokine receptor relies on a tyrosine kinase
protein bound in its cytosolic domain for enzymatic activity. One notable family of
cytokines is the Janus kinase(Jak), they are tyrosine kinase proteins which
transduce cytokine-mediated signals via the JAK-STAT pathway.

References

Alberts, B. et al. (2015). Molecular Biology of the Cell (6thed.). New York, NY, USA::
Garland Science.
Katzung, B. G., Masters, S. B., & Trevor, A. J. (Eds.). (2012). Basic & clinical
pharmacology (12thed.). New York, NY, USA:: Lange Medical Books/McGraw-Hill.
Howland, R. D., Mycek, M. J., Harvey, R. A., &Champe, P. C. (2006).Lippincott's
illustrated reviews: Pharmacology. Philadelphia: Lippincott Williams & Wilkins.
Rang, H. P., Ritter, J. M., Flower, R. J., & Henderson, G. (2014). Rang & Dale's
Pharmacology: With student consult online access. Elsevier Health Sciences.