Soluble and Membrane Proteins

Classical examples are

Hormones, Receptors, and Signal
Transduction

Hormone -Receptor
Interactions
Hormone stems from a Greek term
meaning to spur on.

General
principles

Higher organisms, from the fruit fly to

humans, are comprised of cells.
The cells often unite to form tissue
which come together to form organs
which together make up the
organism.
Cells of an organism do not live in
isolation.
The communication between cells
ultimately controls growth,
differentiation, and metabolic
processes within the organism.
Communication between cells is often by
direct cell to cell contact.
Communication frequently occurs
between cells over short and long
distances.

General principles cont...

In cases of short and long distance

communication, a substance may be released
by one cell and recognized by a different
target cell.

In the target cell, a specific response is

induced.

Cells use an amazing number of signaling

chemicals.

These signaling molecules are termed

hormones.
The ability of a hormone to induce a response in
a target cell is usually mediated by a
hormone receptor on, or in, the target cell.

General characteristics
of hormones

Hormones are molecules synthesized by specific

tissue. Classically these tissue were called
glands.
Hormones are secreted directly into the blood
which carries them to their sites of action.
Hormones are present at very low levels in the
circulatory system.
Hormones specifically affect or alter the
activities of the responsive tissue (target
tissue).
Hormones act specifically via receptors located
on, or in, target tissue.

Hormone/Receptor Interaction
Secondary Signals

Hormone

Range of
possible
pathways

Receptor

Mediator
Protein

Effectors

H1

R1

G1

E1

H2

R2

G2

E2

Possible pathways of transmission of hormonal signal. Each

hormone can work through one or more receptors; each
hormone-receptor complex can work through one or more
mediator proteins (either G proteins or other signaling
mechanism), and each mediating protein or enzyme activated
by hormone-receptor complexes can affect one or more
effectors functions.

The four primary arenas

of hormone action
Growth &
Development

Reproduction

Hormones

Maintenance of
internal
environment

Energy production,
utilization &
storage

Definitions

Endocrine - Refers to the internal secretion of biologically

active substances.
Exocrine - Refers to secretion outside the body, for
example, through sweat glands, mammary
glands, or ducts lead to the gastrointestinal.
Hormone - Substances released by an endocrine gland and
transported through the bloodstream to
another tissue where it acts to regulate
functions in the target tissue (classic
definition).
Paracrine - Hormones that act locally on cells that did
not produce them.
Autocrine - Hormones that act on cells that produced
them.

Receptors -Hormones bind to receptors molecules on cells.

A receptor must specifically recognize the
hormone from the numerous other molecules in
the blood and transmit the hormone binding
information into a cellular specific action.

Endocrine

Blood vessel

Hormone secretion
into blood by
endocrine gland

Distant target cells

Paracrine
Secretory cell

Adjacent target cell

Autocrine

Receptor
Hormone or other extra
cellular signal

Target sites on same cell

Endocrine cell

Neurotransmitter cell
H
H

H
H

H
H

H
R H

Autocrine

R H

H R

H
H
Blood
vessel

Autocrine

H
H

H
N

Axon
Paracrine

R H

N
N

H
R H

Actions of hormones &

neurotransmitters & their
interrelationships
(H,hormone; R, receptor; N,neurotransmitter.)

H
R

N
N
R

H R
Neurotransmitter &
hormone target cell

Examples of Hormones and

glands that produce them

Selected hormones & their functions

Hormone

Source

Principal functions

Insulin

Pancreas

Controls blood-sugar level and storage of glycogen.

Glucagon

Pancreas

Stimulates conversion of glycogen to glucose; raises

blood sugar level.

Oxytocin

Pituitary gland Stimulates contraction of the uterine muscles and

secretion of milk by the mammary glands.

Vasopressin

Pituitary gland Controls water excretion by the kidneys; stimulates

contraction of the blood vessels.

Growth hormone

Pituitary gland Stimulates growth.

Adrenocorticotrophic Pituitary gland Stimulates the adrenal cortex, which,in turn,releases

hormone (ACTH)
several steroid hormones.
Prolactin

Pituitary gland Stimulates milk production by the mammary glands

after birth of baby.

Epinephrine

Adrenal glands

Stimulates rise in blood pressure, acceleration of

heartbeat, decreased secretion of insulin, and
increased blood sugar.

Selected hormones & their functions cont...

Hormone
Cortisone

Thyroxine &

Source

Adrenal glands

Thyroid gland

Triiodothyronine
Calcitonin
Parathyroid

Principal functions

Helps control carbohydrate metabolism, salt

and water balance, formation and storage of
glycogen.
Increases the metabolic rate of carbohydrates
and proteins.

Thyroid gland

Prevents the rise of calcium and phosphate in the

body.
Parathyroid gland Regulates the metabolism of calcium and
phosphate in hormone in the body.

Gastrin

Stomach

Secretin
Estrogen

Duodenum
Ovaries

Progesterone

Ovaries

Stimulates secretion of gastric juice.

Stimulates secretion of pancreatic juice.
Stimulates development and maintenance of
female sexual characteristics.
Stimulates female sexual characteristics and
maintains pregnancy.

Regulation of transcription by hormones that act on

the cell surface.

H R

2nd
Messenger

Modification

Effector

PP

Pre-mRNA

Response
Protein

mRNA

Hormone Receptors
and

Signal Transduction

Hormone Receptors
Nuclear receptors
estrogens

Cytoplasmic receptors

Most steroid and thyroid hormones

Cell surface membrane

receptors
Polypeptide hormones and
catecholamines

Plasma
Membrane

Hormone

Membrane
Effects

Receptor
Cellular
Trafficking
Enzymes

Effector

Secondary Messenger
or Secondary Signal

Activated Inhibited
Nucleus

DNA Synthesis
RNA Synthesis

Protein
Synthesis

A general model for the action of peptide hormones, catecholamines, and

other membrane-active hormones. The hormone in the extra cellular fluid
binds to the receptor and activates associated effector(s) systems, that
may or may not be in the same molecule. This activation results in
generation of an intracellular signal or second messenger that, through a
variety of common and branched pathways, produces the final effects of
the hormone on metabolic enzyme activity, protein synthesis, or cellular
growth and differentiation.

Receptors that span the

membrane Seven times

cAMP

cAMP: synthesis and degradation

cAMP

Amino acid Phosphorylation is very

important in intracellular signal
transduction
ATP
ATP

S Serine
Protein Kinases transfer terminal Phosphate groups
from ATP to Serine, Threonine, or Tyrosine residues
in proteins

Result in activation or inactivation of the recipient protein !

S Serine

Amino acids
that can be
phosphorylated
Threonine

Y Tyrosine

Tyrosine kinase receptors are a family of receptors with a similar

structure. They each have a tyrosine kinase domain (which
phosphorylates proteins on tyrosine residues), a hormone binding
domain, and a carboxyl terminal segment with multiple tyrosines for
autophosphorylation. When hormone binds to the extra cellular domain
the receptors aggregate.

When the receptors aggregate, the tyrosine kinase domains

phosphorylate the C terminal tyrosine residues.

This
with
with
This

phosphorylation produces binding sites for proteins

SH2 domains. GRB2 is one of these proteins. GRB2,
SOS bound to it, then binds to the receptor complex.
causes the activation of SOS.

SOS is a guanyl nucleotide-release protein (GNRP). When this

is activated, it causes certain G proteins to release GDP and
exchange it for GTP. Ras is one of these proteins. When ras
has GTP bound to it, it becomes active.

Activated ras then causes the activation of a cellular kinase

called raf-1.

Raf-1 kinase then phosphorylates another cellular kinase called

MEK. This cause the activation of MEK.

Activated MEK then phosphorylates another protein kinase called MAPK

causing its activation. This series of phosphylating activations is called
a kinase cascade. It results in amplification of the signal.

Among the final targets of the kinase cascade are transcriptions factors (fos
and jun showed here). Phosphorylation of these proteins causes them to
become active and bind to the DNA, causing changes in gene transcription.

Levels of blood sugar

(glucose) regulate secretion
of hormones from
the pancreas
Pancreas secretes
insulin when glucose
levels are high
Insulin binds to
insulin receptors on
fat and muscle and
promotes glucose
uptake
Overall effect: blood glucose
levels return to normal

Glucose Tolerance Test

The Insulin Receptor

Responsible for clearance of glucose
In addition to binding insulin, it
possesses a tyrosine kinase activity
It is involved in many cellular
activities

Glucose Transporter Intracellular Trafficking

Insulin Receptor

Tyrosine
kinase

Insulin-mediated
Insulin-mediatedglucose
glucosetransport
transportsignaling
signalingpathway
pathway
Insulin
IR

Cell membrane

IRS
PI3K

Glut4

Akt

Xiao Chen, 2006

Insulin-mediated glucose transport signaling pathway

Insulin-mediated glucose transport signaling pathway

IR

glucose

Insulin

Cell membrane

IRS
PI3K

Akt

Xiao Chen, 2006

41 grams

Insulin Signaling Pathways by C. Hooper

http://www.abcam.com/index.html?
pageconfig=resource&rid=10602&pid=7

Examples of therapeutics
developed based on these types
of receptors and the associated
tyrosine kinase signaling system
Erbitux Imclone
Iressa - AstraZeneca
Gleevec Novartis
Herceptin - Genentech