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BME2106 - Introduction to

Cellular and Biomolecular


Engineering
Micronutrients, Microenvironment Micronutrients
and Signalling
Dr. Bee Luan KHOO
What can you think of?
blkhoo@um.cityu.edu.hk
G6617

Department of Biomedical Engineering


BME2106 - Introduction to Cellular and Biomolecular Engineering BME, City University of Hong Kong

Micronutrients
•‘Micro’ means small.
•Micro-nutrients are the organic substances required by the body in small
quantities or diminutive compared to macro-nutrients.
•In simple terms, vitamins can be water-soluble vitamins, fat-soluble vitamins
and minerals can be macro-minerals and trace minerals.
VITAMINS A, D, E, AND K are ARE FAT-SOLUBLE VITAMINS A, D, E, AND K are ARE FAT-SOLUBLE

Storage and Solubility: Unlike water-soluble vitamins, fat-soluble


 Vitamin A is critical for vision and it is an essential component of
rhodopsin, a protein that absorbs light in the retinal receptors.
vitamins are stored in fatty tissues and released slowly as
OH needed.
retinoic acid
O
Role in Eye Health: Vitamin A, abundant in foods like carrots and
spinach, aids in maintaining vision, particularly in adjusting to
Storage form of vitamin A O
light changes and supporting night vision, thus safeguarding
retinol retinal against age-related vision loss and eye diseases like cataracts and
H
macular degeneration.

Fat-Soluble Vitamins: stored in the body's fatty tissues.


Sources and Forms: preformed vitamin A (found in animal
products) and provitamin A carotenoids (found in fruits and
vegetables)
5 6

VITAMINS A, D, E, AND K are ARE FAT-SOLUBLE VITAMINS A, D, E, AND K are ARE FAT-SOLUBLE
VITAMINS VITAMINS

Vision Maintenance: Vitamin A is crucial for preserving the Hair Growth: Adequate levels of vitamin A support healthy hair
function of light-sensing cells in the eyes and for the production growth. Deficiency can lead to alopecia, causing hair loss or
of tear fluid, contributing to overall eye health. thinning.
Immune Function: Deficiency in vitamin A can weaken the Reproductive Health: Vitamin A plays a role in maintaining
immune system, fertility and is crucial for fetal development during pregnancy,
Body Growth: Vitamin A is essential for cell growth, particularly Food Sources and Intake: Vitamin A is primarily found in animal-
in children. derived foods such as liver, fish liver oil, and butter.

7 8
VITAMINS D VITAMINS D
 Vitamin D is a general name for vitamins D3 and D2. Their structural
difference is vitamin D2 has a double bond, that vitamin D3 does not
have, in the hydrocarbon chains attached to the five-membered ring. Bone Maintenance: Vitamin D regulates calcium and
phosphorus levels
Calcium Absorption: Vitamin D promotes Vitamin D2 has a double here Immune System Regulation: It strengthens immune function
calcium absorption in the gut, ensuring Sunlight Synthesis: Vitamin D synthesis occurs in the skin upon
adequate serum calcium and phosphate exposure to sunlight.
concentrations, crucial for normal bone
mineralization, growth, and remodeling.
Sunlight Synthesis: is synthesized in the skin
upon exposure to sunlight.

19 19

VITAMINS D VITAMINS D

Deficiency Risks: Risk factors for deficiency include older age, obesity, Once absorbed into the bloodstream, your liver and kidneys change
and diseases affecting fat absorption. Deficiency can result in soft calciferol into calcitriol, which is the biologically active form of
bones, muscle weakness, and increased fracture risk, along with vitamin D. It can also be stored for later use in the form of calcidiol.
impairments in immune function.
Toxicity Concerns: While sun exposure does not cause toxicity,
excessive supplementation can lead to hypercalcemia, characterized
by elevated blood calcium levels.

19 19
VITAMIN E VITAMIN E

Role in Health: works with other nutrients like


vitamin C, B3, and selenium to enhance its
antioxidant effects.
Blood Thinning Effect: In high doses, vitamin E
Antioxidant Properties: Vitamin E, also known as α-tocopherol,
acts as a blood thinner, diminishing clot
serves as a radical inhibitor, protecting nonpolar membranes by
formation and reducing the risk of thrombosis.
neutralizing free radicals generated during fat oxidation. This
Sources and Deficiency: Dietary sources rich in
antioxidant function helps prevent chronic diseases linked to
vitamin E include certain vegetable oils, seeds,
oxidative stress.
and nuts. While deficiency is rare in healthy
Absorption and Storage: Absorbed in the small intestine, vitamin E
individuals, it may occur in conditions affecting
is subsequently stored in the liver for later use.
fat absorption, such as cystic fibrosis or liver
13 disease. 14

VITAMIN K VITAMIN K

Blood Clotting: Vitamin K is essential for proper blood clotting, Deficiency Risks: Unlike some vitamins, vitamin K isn't stored in
obtained from foods like green leafy vegetables and synthesized large amounts in the body. Deficiency can occur rapidly,
by intestinal bacteria. Its coenzyme form, vitamin KH2, plays a particularly in individuals with fat malabsorption conditions like
vital role in this process. celiac disease or those on broad-spectrum antibiotics. High
Bone Health and Heart Disease Prevention: supports bone vitamin A doses may also hinder vitamin K absorption.
health and prevents blood vessel calcification, potentially Impact on Blood Clotting: Mega-doses of vitamin E can
lowering heart disease risk. counteract vitamin K's blood clotting effects.
WHAT IS STEROID?
Structural Composition: Steroids, classified as lipids, consist of a tetracyclic
ring system with designated A, B, C, and D rings. The A, B, and C rings are six-
membered, while D is a five-membered ring. Trans-fused rings are more
common due to their stability.
Biological Importance: including hormone production, cell membrane
formation, and gene regulation. Cholesterol, the most abundant steroid in
animals, serves as the precursor for vitamin D, bile acids, and other steroids.
Physiological Effects: Steroids exhibit unique properties due to their trans-
fused ring structure, enabling interactions with cell receptors. This
interaction can lead to diverse physiological effects, including muscle mass
enhancement, strength improvement, and increased endurance.

 Cholesterol is an important component of cell  Mammals obtain cholesterol from food or


membranes and it modulates the membrane synthesize it in the liver.
fluidity.  Cholesterol, bound to proteins, is transported
to tissues via blood vessels.
 The hydroxyl group on cholesterol interacts  Cholesterol in low-density lipoproteins tends
with the polar head groups of the membrane to deposit and clog arteries.
phospholipids and sphingolipids, while the
bulky steroid and the hydrocarbon chain are
embedded in the membrane, alongside the
nonpolar fatty-acid chain of the other lipids.

 Cholesterol increases membrane packing and


reduces the permeability of the plasma
membrane to neutral solutes, hydrogen ions,
and sodium ions.

23 23
WHAT ARE STEROID HORMONES? (2) Mineralocorticoids
 Many hormones are derivatives of steroid. – cause increased reabsorption of Na+, Cl-,
and HCO3- by the kidneys, leading to an
 Hormones are chemical messengers – organic compounds increase in blood pressure
synthesized in glands and delivered by the bloodstream.
– e.g. aldosterone
 They are usually attached to carrier proteins to target tissues in order
to stimulate or inhibit some process.
 There are 5 classes of steroid hormones: (3) Androgens
– belong to sex hormones and are secreted
primarily by the testes
(1) Glucocorticoids – are responsible for the development of
– are involved in glucose metabolism male sex characteristics during puberty,
– participate in the metabolism of proteins including muscle growth
and fatty acids. – e.g. testosterone
– e.g. cortisone: it has anti-inflammatory
– e.g. 5-dihydrotestosterone: derived from
effect and is used clinically to treat arthritis
testosterone through enzymatic
and other inflammatory conditions.
conversion by 5α-reductase, further
24 contributes to the development of male
secondary characteristics such as growth
22
of facial and body hair, voice deepening,

(4) Estrogens The Microenvironment,


– belong to sex hormones and are
secreted primarily by the ovaries
Stem Cells, and Cancer
– are responsible for the development of
female sex characteristics and regulation
of the menstrual cycle
– e.g. estradiol and estrone

(5) Progestin
– prepares the lining of the uterus for
implantation of an ovum
– is essential for the maintenance of
pregnancy
– e.g. progesterone

23
Why is the microenvironment [1] Tumor immunology

important – [1] tumor immunology 4. Tumour microenvironment

A 3D structure provides a gradient of conditions, leading to heterogeneity

[1] Tumor immunology [1] Tumor immunology

4. Tumour microenvironment 4. Tumour microenvironment

http://wirtzlab.johnshopkins.edu/research/tumor-microenvironment/
Microenvironment – not just the Microenvironment
cells [2] Signaling molecules
G-CSF
Erythropoietin
[2] Signaling • [4] Extracellular matrix G-CSF (Granulocyte-Colony Stimulating Factor): Stimulates
molecules – Collagen neutrophil production in the bone marrow, crucial for immune
G-CSF system restoration post-chemotherapy or transplantation.
Erythropoietin – Fibronectin
Dysregulation can lead to conditions like leukemia.
[3] Cell-cell contact – Laminin Erythropoietin: Produced by the kidneys, stimulates red blood cell
Adherens junctions
Gap Junctions
• [5] Forces production in the bone marrow, maintaining blood oxygen levels.
Desmosomes – Elasticity Used clinically to treat anemia, especially in patients with kidney
disease or undergoing chemotherapy.
– Compression
Clinical Utility: Both G-CSF and Erythropoietin are commonly
– Stiffness employed in clinical settings to manage various conditions,
highlighting their significance in medical treatment.
Maintaining Homeostasis

Microenvironment Microenvironment
[3] Cell-cell contact (next week) [4] Extracellular matrix
Adherens junctions – Collagen, Fibronectin
Gap Junctions
Desmosomes – Laminin

Microenvironment Microenvironment
[4] Extracellular matrix [5] Forces
Collagen: Most abundant protein providing structural
support to tissues. Forms fibers imparting tensile
– Elasticity
strength. In the tumor microenvironment, collagen – Compression
remodeling can impede immune cell infiltration and – Stiffness
promote tumor invasion.
Fibronectin: Glycoprotein crucial for cell adhesion and
migration. Overexpression in the tumor
microenvironment forms networks supporting tumor
growth and angiogenesis.
Laminin: Glycoprotein vital for cell adhesion and
differentiation. A major component of basement
membranes, forming a physical barrier between tissue
compartments. Overexpression contributes to tumor
invasion and metastasis.

Microenvironment Microenvironment
[5] Forces [5] Forces
Elasticity: The ability of a material to deform and return to its Compression: Force exerted on a material when squeezed or
original shape. Changes in tissue elasticity influence cell compressed. In the tumor microenvironment, compression
behavior, migration, and invasion. Tumors, typically stiffer than affects tumor behavior, including angiogenesis and immune
surrounding tissue, promote cell migration and invasion, infiltration. It can also lead to hypoxia, promoting tumor
contributing to drug resistance. aggressiveness.
Microenvironment Stem cell behavior control
[5] Forces Adult stem cells such as intestinal crypt stem cells are tightly
regulated by the environment around them
Stiffness: Resistance of a material to deformation when force is Sometimes mutations cause bad behaviors
applied. In the tumor microenvironment, stiffness influences
cell behavior, proliferation, and differentiation. Tumor stiffness
contributes to drug resistance and limits therapy efficacy.

Stem cell behavior control Blood cell differentiation


Asymmetric Division of Stem Cells:
Stem cells divide asymmetrically, yielding two daughter cells with distinct destinies.
One daughter cell retains its stem cell identity, while the other undergoes differentiation into specialized cell
types like muscle, nerve, or blood cells.
Regulation of Stem Cell Fate:
Factors influencing stem cell fate include signals from the microenvironment or niche, intracellular signaling
pathways, and epigenetic modifications.
Implications of Dysregulated Asymmetric Division:
Dysfunctions in asymmetric cell division mechanisms can result in the accumulation of undifferentiated cells,
potentially leading to tumor formation.

https://www.youtube.com/watch?v=t3g26p9Mh_k
Blood cell differentiation Blood cell differentiation
Granulocyte Colony Stimulating Factor (G-CSF):
G-CSF promotes the development of granulocytes,
• Multipotent stem cells differentiate into a including neutrophils, eosinophils, and basophils, from the
macrophage through a series of steps that are common myeloid progenitor (CMP) cell.
Erythropoietin (EPO):
regulated by signals and transcription factors. EPO specifically stimulates the production of red blood
• The steps involved in the differentiation of a cells
Clinical Applications:
multipotent stem cell into a macrophage are: G-CSF is used to stimulate white blood cell production in
commitment, differentiation, migration, maturation, neutropenic patients, while EPO is employed to treat
and activation. anemia caused by insufficient red blood cells.

• Understanding the molecular mechanisms that


control this process is important for developing new
therapies that target macrophages and improve
patient outcomes.

Case study - Blood cell differentiation [3] Types of Cell interactions


https://www.youtube.com/watch?v=vpYsjMDwsRk
G-CSF and Epo are signaling molecules that initiate signaling Tight junctions
pathways that lead to gene expression and phenotype change Form a fluid and ion impermeable sheet
Transcription and translation
Allows for different functions on different sides of the sheet

Anchoring junctions
Two types: adherens and desmosomes
Built from cadherins (outside) and catenins (inside)
Adherens: attach to actin cytoskeleton
Desmosome (strong): attach to keratin filaments

Gap junctions
Channels between cells
[3] Types of Cell interactions [3] Types of Cell interactions
Tight junctions Anchoring Junctions Overview:
• Seal the gaps Provide mechanical stability and anchor cells to each other or to the
extracellular matrix.
between adjacent Include two main types: adherens junctions and desmosomes.
cells, Adherens Junctions:
Anchor cells together by forming connections with the actin
• Maintaining integrity cytoskeleton.
of epithelial and Built from transmembrane proteins called cadherins and intracellular
endothelial cell layers proteins called catenins.
Important for tissue structural integrity, cell-cell adhesion, and
• Form a fluid and ion signaling.
impermeable sheet Desmosomes:
Provide strong adhesion between cells by forming connections with
• Allows for different cytoskeletal intermediate filaments.
functions on different Composed of transmembrane proteins (desmogleins and
sides of the sheet desmocollins) and intracellular proteins (desmoplakin).
Critical for maintaining tissue integrity, particularly in mechanically
stressed tissues like the skin and heart muscle.

[3] Types of Cell interactions [3] Types of Cell interactions


Anchoring junctions Gap Junctions Overview:
Channels facilitating the
passage of small
molecules and ions
between adjacent cells.
Enable direct
communication and
coordination between
cells.
Composition and Function:
Formed by connexin
proteins.
Allow synchronized
contraction
[3] Types of Cell interactions [4] The Extracellular matrix

[5] Forces [5] Forces


Elastic Fibers in Connective Mechanotransduction and
Tissue Cellular Response to Tissue
• Elastic fibers provide elasticity and resilience to Stiffness
skin and other tissues.
• Composed of elastin and elastin-associated • Cells are able to sense the mechanical properties
microfibrillar proteins that assemble in a complex of their environment, including tissue stiffness or
fiber network. rigidity.
• Multi-step process involved in the formation of • Mechanotransduction involves the conversion of
elastic fibers. mechanical signals into chemical signals within
the cell.
Elastin enables tissues to return to their original position after • Cells can respond to changes in tissue stiffness by
being stretched or compressed, facilitating skin resilience.
changing their shape and gene expression.
[5] Forces Forces
Mechanotransduction and Cellular Cell Sensing Mechanism:
Response to Tissue Stiffness Cells possess the ability to detect variations in tissue
stiffness within their environment.
Function of Integrins:
Responsive Behavior:
transmembrane proteins
In response to changes in stiffness, cells can alter their
transmitting signals to intracellular proteins, regulating
shape and modulate gene expression accordingly.
gene expression, and influencing cell behavior.
Mechanotransduction Signaling:
When cells detect changes in tissue stiffness, integrins
transmit signals to intracellular proteins.
crucial for physiological processes like wound healing
and tissue development.
Implications for Health:
Dysregulation of mechanotransduction pathways can
contribute to diseases like cancer, cardiovascular
issues, and fibrosis.

Forces Cancer
Uncontrolled growth (proliferation)
Experimental Evidence: Invasion into surrounding tissues
Studies with mesenchymal stem cells grown on gels of Metastasis (spread to other areas in body)
differing stiffness reveal distinct differentiation patterns:
Soft environments promote neuronal differentiation Key terms:
(brain-like stiffness). Malignant: Describes cancerous cells or tumors capable
Intermediate environments prompt muscle cell of invading nearby tissues and spreading.
differentiation (muscle-like stiffness). Proto-oncogene: Normal genes involved in cell growth
Stiffer environments stimulate bone cell regulation, which when mutated, can become oncogenes.
differentiation (bone-like stiffness). Oncogene: Mutated or activated genes promoting
uncontrolled cell growth and division, contributing to
cancer development.
Tumor suppressor gene: Genes that normally inhibit cell
growth, but when mutated, lose this ability, facilitating
cancer development.
Communication is important!
Objectives
● Signal transduction
The process by which a cell
responds to an extracellular signal
 What is cell signaling?

 Types of cell signaling?


● Cell signaling
The molecular mechanisms by which
 What is the mechanisms? cells detect and respond to external
stimuli and send messages to other
cells.

Animal cells can signal to Animal cells can signal to


one another in various ways one another in various ways
https://www.youtube.com/watch?v=i3bY-JCYs4A
Endocrine Signaling:  Endocrine
Utilizes hormones released into the bloodstream to
reach distant target cells and bind to specific Hormones as the mediator,
receptors, exerting effects throughout the body. traveling through
Paracrine Signaling: bloodstream
Involves local release of signaling molecules, affecting
nearby cells within a limited area, facilitating
localized responses.
Synaptic Signaling:
Occurs in the nervous system, where neurons release
neurotransmitters at synapses to communicate with
adjacent neurons or muscle cells, enabling rapid and
precise signaling.
Contact-Dependent Signaling:
Requires physical cell-to-cell contact, either through
direct transfer of signaling molecules or activation of
receptors on neighboring cells' surfaces, facilitating
communication in close proximity.
Animal cells can signal to Animal cells can signal to
one another in various ways one another in various ways
 Paracrine  Autocrine
Locally, through Regulated by its own
extrecellular fluid; produced mediators;
e.g. In inflammation, e.g. in some cancer
cells release cells, where they produce
cytokines and signaling molecules that
chemokines to stimulate their own growth
nearby cells, and proliferation,
promoting contributing to tumor
inflammation and progression
recruiting immune
cells to the site of
injury or infection.

Animal cells can signal to Animal cells can signal to


one another in various ways one another in various ways
 Synaptic  Synaptic
Neuronal signaling – Neuronal signaling –
electrical electrical
impulse stimulates the Cellular Response:
release of Binding of
neurotransmitters to
Neurotransmitters
receptors initiates
cellular responses
Neurotransmitter in the postsynaptic
Release: neuron or target
Neurotransmitters are cell, leading to the
chemical messengers propagation of
that diffuse across the electrical signals or
synaptic cleft and bind physiological
to receptors on the changes.
postsynaptic neuron or
target cell.
Animal cells can signal to Endocrine
one another in various ways Focus on higher order vertebrates

Contact-dependent Multiple levels of cell signaling


Involves direct physical contact between cells for signaling. Endocrine
May include transfer of signaling molecules between
1. Cells producing signaling factors are physically separated
adjacent cells or activation of signaling pathways via cell
2. Messenger molecules are secreted
surface receptors.
Physical Interaction Requirement: 3. Carried in blood or extra-cellular fluid
Signaling occurs when cells come into close proximity,
Signaling Mechanisms: Receptor Types:
Contact-dependent signaling can involve various Membrane Receptors:
mechanisms, such as juxtacrine signaling Located on the surface of target cells.
Role in Development: Activate intracellular signaling pathways via signal cascades.
Essential during embryonic development for cell Cytoplasmic Receptors:
differentiation, tissue patterning, and organ formation. Located inside target cells.
Maintains tissue integrity and homeostasis in mature Require specific transport systems to move signaling molecule-
organisms by coordinating cell behavior and functions. receptor complex to nucleus for gene expression activation. 10

2. Nitric oxide (NO) and Carbon Monoxide (CO)


1. Steroid hormones Both are signaling molecules that diffuse across cell membranes.
Act locally to regulate various physiological processes.
NO Mechanism:
This class of molecules diffuse across the plasma membrane and Produced by endothelial and nerve cells.
bind to Receptors in the cytoplasm or nucleus. Alters activity of intracellular target enzymes, such as guanylate cyclase.
They are all synthesized from cholesterol. Involved in blood flow regulation, immune function, and neurotransmission.
CO Mechanism:
Produced by heme oxygenase.
Sex steroids (estrogen, progesterone, testosterone) Similar to NO, regulates physiological processes.
Corticosteroids (glucocorticoids and mineralcorticoids) Involved in blood flow, inflammation, and cell proliferation regulation.
Acetylcholine (ACh) Signaling:
Another local signaling molecule produced by nerve cells.
Thyroid hormone, vitamin D3, and retinoic acid have different Stimulates endothelial cells to produce cGMP, leading to vasodilation.
structure and function but share the same mechanism of action with Regulates nervous system function, including neurotransmission and muscle
the other steroids. contraction.

Steroid Receptor Superfamily.


They are transcription factors that function either as activators or
repressors of transcription.
3. Neurotransmitters 4. Eicosanoids
They signal from neuron to neuron or from neuron to other target cell This class of lipids act as signaling molecules that
(ex. muscle cell ). bind to cell surface molecules.
Acetylcholine: Muscle movement, learning, and memory. They include:
Glycine: Inhibitory neurotransmitter reducing neural activity. Prostaglandins: Regulate inflammation, blood clotting, and blood
Glutamate: Excitatory neurotransmitter increasing neural activity. pressure; protect gastrointestinal tract.
Dopamine: Role in motivation, reward, movement, and attention. Prostacyclins: Regulate blood clotting, dilate blood vessels, and
Epinephrine: Involved in "fight or flight" response, increasing heart bronchodilate in lungs.
rate and blood flow. Thromboxanes: Promote platelet aggregation and blood clotting.
Serotonin: Regulates mood, appetite, and sleep. Leukotrienes: Induce inflammation, especially in the respiratory
Histamine: Involved in immune response, inflammation, and
system; cause airway constriction.
wakefulness.
GABA: Inhibitory neurotransmitter promoting relaxation and reducing
neural activity.
Mode of Action:
Common features: Act in autocrine or paracrine pathways due to rapid breakdown.
hydrophilic molecules that bind to cell surface receptors. Stimulate various responses in target cells, including blood platelet
The binding induces conformational changes that open ion channels aggregation, inflammation, and smooth muscle contraction.
ion fluxes in the cell.

Cells are stimulated for A signal molecule can induce different


different processes responses in different target cells
Receptor protein – receives the extracellular signal
Intracellular signaling molecules – act in sequence and
ultimately later the activity of the effector proteins, which
then affect the behavior of the cell
Major types of cell-surface
Function of Cell Surface
receptors
Receptors
Neurotransmitters:
● ion-channel-coupled receptors converts chemical Activate ligand-gated ion channels on the cell surface.
Directly control ion flux across the plasma membrane.
signals into electrical signals Produce rapid changes in membrane potential of the target cell.
--specific in the nervous system and other electrically Peptide Hormones:
Bind to G-protein-coupled receptors (GPCRs) on the cell surface.
excitable cells (e.g. muscle cells) Activate intracellular signaling pathways through G proteins.
Result in the activation of second messenger systems, such as cyclic AMP (cAMP)
pathway.
● G-protein-coupled receptors (GPCPs) Growth Factors:
-- activates G-protein subunits Bind to enzyme-coupled receptors on the cell surface.
Activate intracellular signaling pathways.
Lead to changes in gene expression and cellular behavior, regulating growth,
proliferation, differentiation, and survival.
● enzyme-coupled receptors -Ligand-gated ion channels that directly control ion flux across the plasma
--enzymatic activity, membrane (NEUROTRANSMITTERS)
e.g. receptor tyrosine kinases (RTKs)
-Other receptors initiate a cascade of events ultimately affecting gene
expression (PEPTIDE HORMONES AND GROWTH FACTORS)

Intracellular response(GPGR) Intracellular response


Cyclic AMP Pathway:
Nature and Function: Extracellular signals activate G-protein-linked receptors, which in turn activate
G protein-coupled receptors (GPCRs) are seven-transmembrane adenylyl cyclase.
domain receptors that detect molecules outside the cell. Adenylyl cyclase produces cyclic AMP (cAMP), which activates protein kinase A
(PKA).
They activate internal signal transduction pathways, leading to cellular PKA then regulates gene transcription, leading to cellular responses.
responses. Inositol Phospholipid Pathway:
Ubiquitous Presence: G-protein-coupled receptors activate phospholipase C (PLC).
GPCRs are found exclusively in eukaryotes, including yeast and PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol
1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
animals. IP3 binds to its receptor on the endoplasmic reticulum, causing a release of
They respond to a diverse array of ligands, ranging from small intracellular Ca2+.
molecules to peptides and large proteins. Intracellular Ca2+ Rise:
Clinical Significance: Increased intracellular Ca2+ activates downstream effectors such as protein kinase
C (PKC) and calmodulin.
Involved in numerous diseases and physiological processes such as Activation of these effectors leads to various cellular responses, including
sensory perception, neurotransmission, and hormone signaling. secretion, contraction, and gene expression.
Approximately 40% of modern medicinal drugs target GPCRs, making
them crucial in pharmacotherapy.
Intracellular response What is
Ras?
o Ras is an oncogene

o Ras is a small GTP-binding protein…it binds


guanine triphosphate

oRas bound to GTP is active…Ras bound to GDP


is inactive

o Ras mutation is implicated in many kinds of cancer…

EGFR and the Ras EGFR and the Ras Pathway


Pathway EGF EGFR Activation and RAS Pathway:
Ligand binding activates EGFR, leading to receptor dimerization and
autophosphorylation.
EGFR Intracellular signaling proteins like Grb2 bind to phosphorylated tyrosine
Grb2
residues on EGFR.
SOS P
RAS P RAS Activation and Downstream Kinases:
GTP Grb2 recruits SOS, which activates RAS by promoting GDP to GTP exchange.
Active RAS triggers downstream kinases in the MAPK/ERK pathway, including
Raf
Grb2: adaptor protein that binds to
Raf, MEK, and ERK.
phosphorylated Tyr on EGFR using Cellular Responses and Mutations:
P its SH2 domain; Downstream kinases phosphorylate transcription factors and target proteins,
MEK SOS binds GTP to activates RAS; promoting cell growth and survival.
RAS binds GTP to activate Raf;
P Raf kinase phosphorates MEKs; Mutations in RAS genes are common in cancer, leading to constitutive pathway
ERK MEKs phosphorylate ERKs; activation and tumor development.
ERK kinases further phosporylate other target Therapeutic Implications:
proteins and translolate to nucleus to activate
a bounch of genes for cell growth and survival
Targeting EGFR and RAS signaling is crucial in cancer treatment, with
inhibitors developed to disrupt pathway activation.
This approach aims to inhibit abnormal cell growth and survival driven by
PROLIFERATION CELL SURVIVAL
dysregulated signaling pathways.
. Aaronson, Growth factor and receptor tyrosine kinases. Sci. STKE 2005, tr6 (2005).
EGFR and the Ras Pathway

A. Chan, Ras-MAPK Pathways. Sci. STKE 2005, tr5 (2005).

Ras Mutations display Tumor Specificity


EGFR and the PI3K pathway
Pancreatic Carcinoma K-Ras codon 12 (GGTgly) >GTTval PI3K Pathway in Cell Survival and Cancer:
PI3K pathway activation promotes cell survival and is frequently observed in cancer
cells.
PI3K phosphorylates PIP2 to generate PIP3, initiating downstream signaling cascades
Lung carcinoma K-Ras codon 12 (GGTgly) >AGTser that regulate cell survival.
EGFR Interaction with PI3K:
EGFR interacts with the p85 subunit of PI3K, facilitating PI3K recruitment to the
plasma membrane and its subsequent activation.
Activated PI3K signaling through Akt promotes cell survival and contributes to cancer
progression.
Bladder Carcinoma H-Ras codon 12 (GGCgly) >GTCval Impact of EGFR Mutations:
EGFR mutations can enhance PI3K signaling, leading to constitutive EGFR activation
and increased cell survival.
This mechanism of increased PI3K signaling is implicated in resistance to EGFR-
targeted cancer therapies.
Therapeutic Implications:
Melanoma N-Ras codon 61 (CAAgln)>CGAarg Understanding the role of EGFR and the PI3K pathway in cancer informs the
development of targeted therapies.
Targeting components of the PI3K pathway presents potential strategies for
overcoming resistance to EGFR-targeted therapies and improving treatment outcomes
in cancer patients.
A. Chan, Ras-MAPK Pathways. Sci. STKE 2005, tr5 (2005).
Consequences of Receptor Tyrosine
EGFR and the PI3K pathway Kinase (RTK) activation
GROWTH
FACTOR
RTK Activation and Cellular Responses:
PIP3 PIP3
Activation of Receptor Tyrosine Kinases (RTKs) induces cellular
RTK
responses such as proliferation, cell survival, and protein synthesis.
P P P Mechanism of RTK Activation:
Akt PDK1
p85
p110 PI3K
Ligand binding to RTKs triggers receptor dimerization and subsequent
autophosphorylation of tyrosine residues, which serve as docking
sites for downstream signaling molecules.
Downstream Signaling Pathways:
RTK activation initiates downstream signaling pathways, including
P P P P P
BAD MDM2
PI3K/Akt for cell survival and Ras/MAPK for proliferation and protein
NF-ĸB FKHR GSK3
synthesis.
Diverse Cellular Effects:
The activation of RTKs can lead to a wide range of cellular effects
depending on the specific downstream signaling pathways that are
activated.
CELL SURVIVAL
. Aaronson, Growth factor and receptor tyrosine kinases. Sci. STKE 2005, tr6 (2005).

Consequences of Receptor Tyrosine PI3K/Akt Defects in


Kinase (RTK) activation GF RTK

GROWTH
Cancer Cancer Syndromes
FACTOR
PIP3 p

PI3-K Lipid Kinase GI, Br, Ov


PIP3 PIP3
RTK

SOS Grb2 RAS


RAS P P P
p85 Akt PDK1 Akt1/2 Ser/Thr Kinase PANC
p110 PI3K

Hamartin Tuberin
Raf (Tuberous Sclerosis TSC1 TSC2
Complex)
P
(Ras-homology
MEK
P P P P P P
enriched in brain)
RheB Inhibitors to PI3K and/or
P
BAD NF-ĸB FKHR MDM2 GSK3 p70S6K Akt are being developed
(Target of rapamycin) mTOR for patient use
ERK

S6K 4EBP-1

PROLIFERATION CELL SURVIVAL PROTEIN SYNTHESIS Protein synthesis

Cell growth/size/survival Kovich & Cohen (2004) Dematology Online Journal 10: 3.
. Aaronson, Growth factor and receptor tyrosine kinases. Sci. STKE 2005, tr6 (2005). Perelman (2004) Dematology Online Journal 10: 17.
Crosstalking among different
signaling REFERE
pathways NCES
1. P. Y. Bruice, Organic Chemistry, Pearson Education,
New Jersey, 5 ed., 2007.
th

2. A. Bruce, D. Bray, K. Hopkin, A. Johnson, J. Lewis,


M. Raff, K. Roberts and P. Walter, Essential Cell
Biology, Garland Science, 2nd ed., New York, 2004.
3. For the information of trans fat:
http://www.cfs.gov.hk/english/faq/faq_13.html
4. For the information of vitamins (Webpage of
National Institutes of Health): http://ods.od.nih.gov/
5. David L Nelson, Michael M. Cox, Lehninger
Principles of Biochemistry, Freeman, 6th ed., 2013.
6. 1. P. Y. Bruice, Organic Chemistry, Pearson
Education, New Jersey, 5th ed., 2007 (Chapter 5 98

and 21).

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