1. kinase receptors &
Nuclear receptor
Aqib Naseer
M Pharm 1st Semester, Pharmacology
SPER, Jamia Hamdard

2. Contents :
1. kinase receptor
Introduction & Structure .
Types of kinase receptors.
Underlying Phosphorylation & signaling pathways involved.
2. Nuclear receptors
Introduction & Structure .
Types of kinase receptors.
Control of gene transcription.
3. References

3. • kinase-linked and related receptors are receptors responding mainly to protein mediators
including
ogrowth factors ,
ocytokines ,
ohormones such as insulin & leptin.
• Effects by these receptors are exerted mainly at the level of gene transcription.
• These receptors comprise of an :
1. an extracellular ligand-binding domain.
2. Intracellular domain .
Both are linked to each other by a single transmembrane helix.
Introduction

4. or extracellular
domain
Or Intracellular domain
Different domains of kinase receptor

5. • In many cases, the intracellular domain is enzymic in nature with :-
1. Protein kinase activity.
2. Guanylyl cyclase activity.
Mainly
tyrosine

6. • This class of receptors i.e tyrosine kinases include insulin ,
ocytokines,
oGrowth factors,
oEGF (epidermal growth factor),
oPDGF, and
oephrins. etc
• They play a major role in controlling cell divison ,
oGrowth , differentiation,
oinflammation ,
otissue repair,
oapoptosis & immune responses.

7. The main types are as follows :
1. Receptor tyrosine kinases (RTKs) .
2. Cytokine receptors.
3. Serine/threonine kinases.

8. Receptor tyrosine kinases (RTKs) :
• These receptors incorporate a tyrosine kinase moiety in the intracellular region.
• They include receptors for many growth factors, such as
oepidermal growth factor ,
onerve growth factor, and
oAlso the group of Toll-like receptors . The insulin receptor also belongs to the RTK class,
although it has a more complex dimeric structure.

9. Phosphorylat
ion of
domains
form docking
site Grb2
protein
Phosphorylation leads
to activation of :
Ras/MAPK cascade.
Or
Cytokine (Jak/Stat)
pathway.
Several other
pathways also exist
Tyrosine kinase receptor

10. 2) Cytokinereceptors :
• These receptors lack intrinsic enzyme activity.
• When occupied, they associate with, and activate, a cytosolic tyrosine
kinase such as Jak (the Janus kinase) or other kinases.
• Ligand for these receptors include cytokines such a interferons and
colony-stimulating factors involved in immunological responses.

11. Recruitment
the Jaks to
the
cytoplasmic
tails of the
receptor
The
phosphorylated
STATs dimerise &
translocate to the
nucleus and
regulate
transcription.
Cytokine receptor
Jaks
transphosphorylat
e and lead to the
phosphorylation
of the STATs.

12. 3. Serine/threonine kinases : This smaller class is similar in structure
to RTKs but phosphorylate serine and/or threonine residues rather
than tyrosine.
• The main example is the receptor for transforming growth factor
(TGF).

13. Protein phosphorylation and kinase
cascade mechanisms in general :
• Generally ligand binding to the receptor leads to dimerisation.
• The association of the two intracellular kinase domains allows a mutual
autophosphorylation of intracellular tyrosine residues to occur.
• The phosphorylated tyrosine residues then serve as high-affinity docking sites
for other intracellular proteins that form the next stage in the signal
transduction cascade. One important group of such ‘adapter’ proteins is known
as the SH2 domain proteins.
• Molecules recruited to phosphotyrosine-containing proteins by their SH2
domains include PLCγ, the activity of which raises intracellular levels of Ca2+
and activates Protein kinase C.

14. Nuclear receptor :
• These are receptors that regulate gene transcription.
• The term nuclear receptors is something of a misnomer,
because some are actually located in the cytosol and migrate
to the nuclear compartment when a ligand is present.
• They include receptors for
• steroid hormones,
• thyroid hormone and other agents such as retinoic acid and
• vitamin D.
Nuclear receptor as a
polypeptide

15. • Keypoints nuclear receptors :
1. Receptors for steroid hormones such as oestrogen and the glucocorticoids
are present in the soluble phase of cytoplasm of cells and are translocated
into the nucleus after binding with their steroid partner.
2. NR family can be considered as ligand-activated transcription factors that
transduce signals by modifying gene transcription.
3. Unlike other receptors the nuclear receptors are not embedded in
membranes but are present in the soluble phase of the cell.

16. 3. Some, such as the steroid receptors, become mobile in the presence of their
ligand and can translocate from the cytoplasm to the nucleus.
4. Others such as the RXR (retinoid receptor) probably dwell mainly within the
nuclear compartment. Some NRs, while unliganded, act to constitutively repress
some genes (e.g. RXR).

17. Structure of nuclear receptors :
• All the nuclear receptors contain three important domains in a single
polypeptide with some modifications found :
1. A ligand binding domain (N terminal domain).
2. A DNA binding domain (zinc fingers containing region ) and
3. N-terminal activation region (transcriptional regulation domain).

18. Structure of nuclear receptor

19. • All NRs are monomeric proteins that share a broadly similar structural design
viz :-
1. The C-terminal domain contains the ligand binding module and is specific
to each class of receptor.
2. The core domain of the receptor is highly conserved and consists of the
structure responsible for DNA recognition and binding. At the molecular
level, this comprises two zinc fingers .
3. Finally, the N-terminal domain contain an activation region (AF-1) essential
for transcriptional regulation .

20. • The C-terminal half of the molecule contains a hinge region (which can be
involved in :
I. Binding DNA,
II. the domain responsible for binding the hormone or ligand (the LBD), and
III. specific sets of amino acid residues for binding coactivators and
corepressors in a second activation region (AF-2).
• The N-terminal activation region (AF-1) is subject to regulation by
phosphorylation and other mechanisms that stimulate or inhibit
transcription.

21. CLASSIFICATION OF NUCLEAR
RECEPTORS :
• The NR superfamily consists of two main classes (I and II), together with a third
that shares some of the characteristics of both .
1. Class I :
• consists largely of receptors for the steroid hormones, including the
glucocorticoid and mineralocorticoid receptors (GR and MR), as well as the
oestrogen, progesterone and androgen receptors (ER, PR and AR, respectively).
• ligand partner binds to their NR with high affinity. These liganded receptors
generally form homodimers and translocate to the nucleus, where they can
transactivate or transrepress genes by binding to ‘positive’ or ‘negative’
hormone response elements.

22. ER : oestrogen receptor , MR : mineralocorticoid receptor , TR
FXR: farnesoid receptor , PR : prolactin receptor
GR :glucocorticoid receptor ,PPAR : peroxisome proliferator receptor
LXR :liver oxysterol receptor ,RXR:retinoid receptor , : TR : thyroid receptor

23. • Class II :
• Their ligands are generally lipids already present to some extent within the cell.
• This group includes the peroxisome proliferator-activated receptor (PPAR)
that recognises fatty acids; the liver oxysterol receptor (LXR) that recognises
and acts as a cholesterol sensor.
• Unlike the receptors in class I, these NRs almost always operate as
heterodimers together with the retinoid receptor (RXR).
• They tend to mediate positive feedback effects (e.g. occupation of the receptor
amplifies rather than inhibits a particular biological event).

24. Rxr class II homodimer receptor :
• When class II monomeric receptors bind to RXR, two types of heterodimer may
be formed:
1. non -permissive heterodimer, which can be activated only by the RXR ligand
itself, and the
2. permissive heterodimer, which can be activated either by retinoic acid itself
or by its partner’s ligand.

25. 3. A third group of NRs :
• is really a subgroup of class II in the sense that they form obligate heterodimers
with RXR, but rather than sensing lipids, they play a part in endocrine signalling.
• The group includes the thyroid hormone receptor (TR), the vitamin D receptor
(VDR) and the retinoic acid receptor (RAR).

26. Control of gene transcription through
nuclear receptors :
• Hormone response elements are the short sequences
of DNA to which the nuclear receptors bind to modify
gene transcription.
• Once in the nucleus, the ligand-bound receptor
recruits further proteins including
co-activators or co-repressors to modify gene expression through its AF1 and
AF2 domains.
• Co-activators are enzymes involved in chromatin remodelling such as histone
acetylase/deacetylase which, together with other enzymes, regulate the
unravelling of the DNA to facilitate access by polymerase enzymes and hence
gene transcription.

27. • Some unliganded class II receptors such as TR and Vitamin D Receptor are
constitutively bound to these repressor complexes in the nucleus, thus
‘silencing’ the gene. The complex dissociates on ligand binding, permitting an
activator complex to bind.
• Much remains to be discovered about this interesting and complex family of
receptor proteins.

28. Thank you

29. References :
• Rang & Dales”s Pharmacology 7th edition / chapter 3 / How Drugs act –
molecular mechanisms
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578364/
• Goodman’s & Gillmans the pharmacological basis of therapeutics 13th edition
,Laurence L brunton , Randa hilal dandan , bjorn c knollmen….
Pharmacodynamics: Molecular Mechanisms of Drug Action . page 31, Donald
K. Blumenthal.