5 Arciaga, Frances Geline R.

1MD – Section 1
Topic: HORMONE ACTION AND SIGNAL TRANSDUCTION
April 13, 2020

Questions:
1. Explain how hormones affect homeostatic mechanisms.
2. Summarize signal generation.
3. Illustrate how hormone-receptor interactions activate phospholipase C (PLC).
4. Summarize the insulin signaling pathways.
5. Discuss the role and significance of the hormone response transcription unit.
6. What is the nuclear receptor superfamily?

1. Explain how hormones affect homeostatic mechanisms.

Homeostasis is the regulation of the internal conditions within cells and whole
organisms such as temperature, water, and sugar levels. This keeps cells and
organisms functioning at optimal levels even when challenged by internal and external
changes. The functioning of these diverse cells must be regulated and co-ordinated,
and, therefore, must be able to communicate with one another. The body systems that
facilitate cellular communication and control are the nervous and endocrine systems.
Homeostasis depends on the close relationship between the nervous system and the
endocrine system. Nervous system messages tend to be transmitted rapidly to precise
locations in the body. In addition to cellular communication through neurons, the body
secretes chemical messengers from glands. Endocrine glands secrete chemical
messengers called hormones directly into the bloodstream, which transports the
hormones throughout the body. When hormones reach their target cells, interaction with
these cells sets in motion specific regulatory responses.
Each target cell contains receptor proteins. Circulating hormones bind to their
specific receptor proteins, like a key that fits into a lock. For example, human growth
hormone (hGH) circulates in the bloodstream and interacts with liver, muscle, and bone
cells. Each of these cell types contains receptor proteins specifi cally shaped to bind
with hGH. When the hormone binds to its receptor, this triggers other reactions in the
target cell. In other words, the target cell receives and responds to the chemical
message sent by the hormone.

Overview of some endocrine glands, the hormones they release, and their effects on
target tissues and organs.
 2. Summarize signal generation.
Hormones activate target cells by diffusing through the plasma membrane of the
target cells (lipid-soluble hormones) to bind a receptor protein within the cytoplasm of
the cell, or by binding a specific receptor protein in the cell membrane of the target cell
(water-soluble proteins). In both cases, the hormone complex will activate a chain of
molecular events within the cell that will result in the activation of gene expression in the
nucleus. The reaction of the target cells may then be recognized by the original
hormone-producing cells, leading to a down-regulation in hormone production. This is
an example of a homeostatic negative feedback loop.
Steps of Hormonal Signaling

o Biosynthesis of a particular hormone in a particular tissue.

o Storage and secretion of the hormone.

o Transport of the hormone to the target cells, tissues, or organs.

o Recognition of the hormone by an associated cell membrane or an intracellular

receptor protein.

o Relay and amplification of the received hormonal signal via a signal transduction
process.

o Potential feedback to a hormone-producing cell.

Water - soluble hormone

receptor activation: Water-
soluble hormones, such as
epinephrine, bind to a cell-
surface localized receptor,
initiating a signaling cascade
using intracellular second
messengers.
 3. Illustrate how hormone-receptor interactions activate phospholipase C
(PLC).
Phospholipase (PLC) activation appears to involve a specific G protein, which also
may activate a calcium channel. Phospholipase C generates inositol trisphosphate
(IP3), which liberates stored intracellular Ca2+, and diacylglycerol (DAG), a potent
activator of protein kinase C (PKC). In this scheme, the activated PKC phosphorylates
specific substrates, which then alter physiologic processes. Likewise, the Ca2+–
calmodulin complex can activate specific kinases, two of which are shown in the image
below. These actions result in phosphorylation of substrates, and this leads to altered
physiologic responses. This image also shows that Ca2+ can enter cells through
voltage- or ligand-gated Ca2+ channels. The intracellular Ca2+ is also regulated
through storage and release by the mitochondria and endoplasmic reticulum.
 4. Summarize the insulin signaling pathways.
The insulin signaling pathway is the sum of all proteins involved in the action of
insulin in the body and the factors that regulate this pathway. It regulates glucose
homeostasis by controlling important processes such as glucose and lipid metabolism.
The main function of this pathway is to assist insulin in regulating blood glucose
homeostasis in the body while working along with glucagon.
The insulin receptor (InsR) is a tetramer, connected by two  and two  subunits
via disulfide bonds. The two  subunits which are located on the outside of the
cytoplasmic membrane are responsible for binding insulin; while the two  subunits are
the transmembrane proteins that act as a signal transducer. Insulin binds to the 
subunit of the insulin receptor on the target cells, changing the conformation of the 
subunit and thereby activating tyrosine kinase. This evokes auto-phosphorylation of the
 subunit, which subsequently leads to phosphorylation of intracellular proteins called
insulin receptor substrates (IRS). The phosphorylation of IRS1 or IRS2 activates
PI3K/Akt signaling pathway and Ras-Raf-MEK-MAPK signaling pathway.
The PI3K / Akt Signaling Pathway
The regulatory effect of insulin on metabolism is mainly mediated by the
phosphoinositol 3 kinase pathway or the PI-3K pathway. After PI3K activation by IRS1,
the activated PI3K catalyzes the phosphorylation of phosphatidylinositol across the
membrane to produce PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3
(phosphatidylinositol 3,4,5-triphosphate). PIP3 acts as a second messenger to recruit
Akt and PDK1 (3-phosphoinositide dependent protein kinase-1) into the envelope region
(PTEN pathway), where phosphorylation of PDK1 activates the serine / threonine
residues of Akt. Akt regulates the translocation of the insulin-sensitive glucose
transporter Glut4 within muscle and fat cells to the cell membrane for the extraction of
glucose. Akt also phosphorylates glycogen synthase kinase, deactivating the enzyme,
and inhibiting the activity of glycogen synthase. Gsk-3 also inactivates eukaryotic
promoter 2B, promoting the synthesis of protein-mediated by insulin. Insulin is
phosphorylated by mTOR (molecular target of rapamycin) kinase and 4E-BPI, which
promotes protein synthesis at the translation level. Meanwhile, this pathway also
mediates the survival pathway of beta cells, which is closely related to the growth,
proliferation, differentiation, and apoptosis of beta cells.

The MAPK Signaling Pathway

The MAPK pathway is activated when Grb2 (growth factor receptor-bound
protein 2) binds to tyrosine-phosphorylated Shc (Sh2-containing collagen-related
protein) or via Sh2 binding to insulin receptors. Grb2 is linked to mammalian nucleotide
exchange factor mSOS. mSOS is a nucleotide exchange protein that promotes the
conversion of GDP into GTP on Ras and activates Ras. P21Ras protein is anchored to
the membrane by farnesienase, and Raf is recruited to the membrane and activated.
Raf activates MAPK/Erk kinase (MEK). Extracellular signal-regulated kinase 1/2
(ERK1/2) regulates transcription factors associated with cell proliferation nucleus (ELK1,
FOS) and EMT (Twist, ZEB1) to activate a variety of cancer gene and cell cycle
regulatory proteins, promoting cell division, protein synthesis, and cell growth. And
insulin also phosphorylates glycogen synthesis kinase-3β (GSK3β) and inactivates it,
thereby activating oncogenes & transcription factors and promoting cell proliferation.
5. Discuss the role and significance of the hormone response transcription
unit.
The hormone response transcription unit is an assembly of DNA elements and
complementary, cognate DNA-bound proteins that interact, through protein–protein
interactions, with a number of coactivator or corepressor molecules. An essential
component is the hormone response element that binds the ligand ()-bound receptor
(R). Also important are the accessory factor elements (AFEs) with bound transcription
factors. More than two dozen of these accessory factors (AFs), which are often
members of the nuclear receptor superfamily, have been linked to hormone effects on
transcription. The AFs can interact with each other, with the liganded nuclear receptors,
or with coregulators. These components communicate with the basal transcription
machinery, forming the Polymerase II PIC (ie, RNAP II and GTFs) through a coregulator
complex that can consist of one or more members of the p160, corepressor, mediator-
related, or CBP/p300 families. Many of the transcription coregulators carry intrinsic
enzymatic activities that covalently modify the DNA, transcription proteins, and the
histones present in the nucleosomes (not shown here) in and around the enhancer
(HRE, AFE) and promoter. Collectively the hormone, hormone receptor, chromatin,
DNA and transcription machinery integrate and process hormone signals to regulate
transcription in a physiological fashion.
 6. What is the nuclear receptor superfamily?
Nuclear receptors take part in different roles in metabolic homeostasis,
eukaryotic development, differentiation and reproduction. The nuclear receptor super-
family consist of proteins that are single polypeptide chains with three major domains: a
variable amino-terminal domain, a highly conserved DNA-binding domain (DBD), and a
less conserved carboxyl-terminal ligand binding domain (LBD). AF: activation function
(domain 1 and 2). H: hinge. 

The nuclear superfamily is subdivided into three classes:

1. Class 1 - Steroid Receptor Family:

a. progesterone receptor (PR)
b. estrogen receptor (ER)
c. glucocorticoid receptor (GR)
d. androgen receptor (AR)
e. mineralocorticoid receptor (MR)
Steroid receptors are bound to Hsps in the cytoplasm. Upon binding ligands,
the free receptors translocate to the nucleus and bind as homodimers to
imperfect palindromic response elements at upstream promoter sites. 

2. Class 2 – Thyroid / Retinoid Family

a. thyroid receptor (TR)
b. vitamin D receptor (VDR)
c. retinoic acid receptor (RAR)
d. peroxisome proliferator-activated receptor (PPAR)
The class 2 nuclear receptors typically function as heterodimers. The
heterodimers are bound to their response element regardless of whether ligands
are present and in the absence of heat shock proteins. 
 3. Class 3 - Orphan Receptor Family
This class of nuclear receptor comprises a set of proteins sharing significant
sequence homology to known nuclear receptors, but for which the ligands have
not yet been identified. Orphan nuclear receptor offers a unique system for the
discovery of novel signaling pathways that could provide new drug targets for the
treatment of a variety of human diseases.

References:
https://www.yourhormones.info/students/topics/homeostasis/
http://standring.weebly.com/uploads/2/3/3/5/23356120/13_inquirybio_ch13.pdf
https://courses.lumenlearning.com/boundless-ap/chapter/hormones/
https://www.ncbi.nlm.nih.gov/books/NBK538498/
https://www.cell.com/cell/pdf/S0092-8674(12)00103-1.pdf
https://www.cusabio.com/pathway/Insulin-signaling-pathway.html
https://www.abcam.com/pathways/overview-of-insulin-signaling-pathways
https://www.creative-diagnostics.com/insulin-signaling-pathway.htm
https://www.abcam.com/content/the-nuclear-receptor-super-family-6
Harper’s Illustrated Biochemitry, 30th Edition