Chapter 14
Signal Transduction
Mechanisms: II.
Messengers and Receptors
• Cell-to-cell Communication is absolutely essential
and important for multicellular organisms.
– Cells must communicate to coordinate their
activities.
• Biologists have discovered some universal
mechanisms of cellular regulation, involving the
same small set of cell-signaling mechanisms.
• Cells may receive a variety of signals, such as
chemical signals, electromagnetic signals, and
mechanical signals.
• The process by which a signal on a cell’s surface is
converted into a specific cellular response is a
several steps in a signal-transduction pathway.
Signal Transduction Mechanisms
II. Messengers and Receptors
 • Chemical Signals and Cellular Receptors
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•
•
•
•
G Protein-Linked Receptors
Protein Kinase-Associated Receptors
Growth Factors as Messengers
The Endocrine and Paracrine Hormone Systems
Cell Signals and Apoptosis
Chemical Signals and Cellular Receptors
• Different types of chemical signals can be
received by cells
• Receptor binding involves specific interactions
between ligands and their receptors
• Receptor binding activates a sequence of signal
transduction events within the cell
• All cells have some ability to sense and
respond to specific aspects of their
environment
– Physical factors: light (retina), sound (hair
cells), heat, or gravity
– Chemical factors: extracellular molecularreceptor on tongue
– One cell can release chemical signals that
are recognized by another cells, either
nearby or at a distant location
Different Types of Chemical Signals
Can Be Received by Cells
• Chemical signals
– Hormones: produced at great distances from their target
tissues and carried in the circulatory system to various sites
– Growth factors: released locally, acting on nearby tissue
• Many messengers are Hydrophilic Compounds:
– First messenger: Ligand
– Second Messenger: such as cyclic AMP and calcium
– Signal transduction: the ability of a cell to translate a
Receptor-Ligand Interaction to change in its behavior or
gene expression
• Hydrophobic messengers
– Act on nuclear receptors or cytosol, regulate the transcription
of particular genes
– Steroid hormones
Receptor Binding Involves Specific Interactions
Between Ligands and Their Receptors
• How do cells distinguish messengers from the environment
– Highly specific way: the messenger molecule binds to the receptor
– A messenger forms noncovalent chemical bonds with the receptor
protein alteration
• Receptor Affinity- Kd: dissociation constant
• Receptor Down-Regulation: desensitization is due mainly
to changes in the properties or cellular location of the
receptor
 Removal of the receptor from the cell surface: receptor-mediated
endocytosis
 Alteration to the receptor that lower its affinity for ligand
 Alteration to the receptor that render it unable to initiate change in
cellular function
• Nasal spray: receptor down-regulation
Signal Transduction Mechanisms
II. Messengers and Receptors
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•
•
•
•
•
Chemical Signals and Cellular Receptors
G Protein-Linked Receptors
Protein Kinase-Associated Receptors
Growth Factors as Messengers
The Endocrine and Paracrine Hormone Systems
Cell Signals and Apoptosis
Two Classes of G Protein
• Large heterotrimeric G proteins
– G: largest one bind to GTP or GDP
– G and G always bind together
– GTP-G , GTP-G  regulate different processes
– Gs or Gi
• Small monomeric G proteins
– Ras related to
• Tyrosine kinase receptor
• Cytoskeleton
• Activate ion channel or enzyme activity
• Different effects of cAMP concentration
– Breakdown of glycogen in muscle or liver
cells
– Increase heart contraction
– Inhibit the movement of blood platelets
– Increase the secretion of salts and water in
intestinal epithelial cells
Disruption of G Protein Signaling
Causes Several Human Diseases
• Salts and fluid in the intestine are regulated by hormones
that act through the G protein Gs to alter intracellular
levels of cAMP
• Certain microbes cause disease by disrupting the Gprotein signaling pathways
– The cholera bacterium, Vibrio cholerae (霍亂弧菌), colonizes
the the small intestine and produces a toxin that modifies a G
protein that regulates salt and water secretion.
– The modified G protein is stuck in its active form,
continuously stimulating productions of cAMP.
– This causes the intestinal cells to secrete large amounts of
water and salts into the intestines, leading to profuse diarrhea
and death if untreated.
• Because cytosolic Ca2+ is so low, small changes
in the absolute numbers of ions causes a
relatively large percentage change in Ca2+
concentration.
The Release of Calcium Ions is a Key
Event in Many Signaling Processes
• Many signal molecules in animals induce responses in
their target cells via signal-transduction pathways that
increase the cytosolic concentration of Ca2+.
– Signal-transduction pathways trigger the release of Ca2+ from
the cell’s ER.
• The pathways leading to release involve still other
second messengers, diacylglycerol (DAG) and inositol
trisphosphate (IP3).
– Both molecules are produced by cleavage of certain
phospholipids in the plasma membrane.
• Cells use Ca2+ as a second messenger in both G-protein
pathways and tyrosine-kinase pathways.
Calcium Oscillation
• Neurons
• Fertilized Mammalian Eggs
• Opening and Closing of Stomata (氣孔) in Plants
Signal Transduction Mechanisms II.
Messengers and Receptors
•
•
•
•
•
•
Chemical Signals and Cellular Receptors
G Protein-Linked Receptors
Protein Kinase-Associated Receptors
Growth Factors as Messengers
The Endocrine and Paracrine Hormone Systems
Cell Signals and Apoptosis
Most Signal Receptors are Plasma
Membrane Proteins
• Most signal molecules are water-soluble and too
large to pass through the plasma membrane.
• They influence cell activities by binding to
receptor proteins on the plasma membrane.
– Binding leads to change in the shape of the receptor
or to aggregation of receptors.
– These trigger changes in the intracellular
environment.
• Three major types of receptors are G-proteinlinked receptors, tyrosine-kinase receptors, and
ion-channel receptors.
Receptor Tyrosine Kinase Aggregate
and Undergo Autophosphorylation
• The tyrosine-kinase receptor system is
especially effective when the cell needs to
regulate and coordinate a variety of activities
and trigger several signal pathways at once.
• Extracellular growth factors often bind to
tyrosine-kinase receptors.
• The cytoplasmic side of these receptors
function as a tyrosine kinase, transferring a
phosphate group from ATP to tyrosine on a
substrate protein.
Protein Kinase-Associated Receptors
• Receptor tyrosine kinases aggregate and undergo autophosphorylation
– Add phosphate groups to particular amino acids
– Trigger a chain of signal transduction event- lead to cell growth,
proliferation or differentiation.
• Receptor tyrosine kinases initiated a signal transduction cascade
involving Ras and MAP kinase:
– GNRP (guanine-nucleotide release protein) = Sos + GRB2
• SH2 domain
– Ras: small monomeric G protein – the growth of cells.
– MAPK (MAP kinase): mitogen-activated protein kinases
– AP-1: Transcription Factor
• Receptor tyrosine kinases activate a variety of other signaling pathway
– PLC: phospholipase C (磷脂酶C)
• PLC-: activated by receptor tyrosine kinase
• PLC-: activated by G protein-linked receptors
• Ligand-gated ion channels are very important in
the nervous system.
– Similar gated ion channels respond to electrical
signals.
Signal Transduction Mechanisms II.
Messengers and Receptors
•
•
•
•
•
•
Chemical Signals and Cellular Receptors
G Protein-Linked Receptors
Protein Kinase-Associated Receptors
Growth Factors as Messengers
The Endocrine and Paracrine Hormone Systems
Cell Signals and Apoptosis
A Signal Molecule Binds to a Receptor
Protein Causing the Protein to Change Shape
• A cell targeted by a particular chemical signal has a
receptor protein that recognizes the signal molecule.
– Recognition occurs when the signal binds to a specific
site on the receptor because it is complementary in
shape.
• When ligands (small molecules that bind specifically to
a larger molecule) attach to the receptor protein, the
receptor typically undergoes a change in shape.
– This may activate the receptor so that it can interact
with other molecules.
– For other receptors this leads to aggregation of
receptors.
Signal Transduction Mechanisms II.
Messengers and Receptors
•
•
•
•
•
•
Chemical Signals and Cellular Receptors
G Protein-Linked Receptors
Protein Kinase-Associated Receptors
Growth Factors as Messengers
The Endocrine and Paracrine Hormone Systems
Cell Signals and Apoptosis
In contrast to growth factors, hormone often
act over large distance via circulatory system
• Hormone differ in many ways
– Steroids or other hydrophobic molecule:
intracelllular receptor
– Adrenergic hormones (腎上腺荷爾蒙):
G-protein link receptor
– Insulin: ligands for receptor tyrosine
kinase
• Act on the target cells: adrenal gland (腎上
腺) – epinephrine (腎上腺素)
Exocrine外分泌
• Digestive tissue/system (消化系統)
Signal Transduction Mechanisms II.
Messengers and Receptors
•
•
•
•
•
•
Chemical Signals and Cellular Receptors
G Protein-Linked Receptors
Protein Kinase-Associated Receptors
Growth Factors as Messengers
The Endocrine and Paracrine Hormone Systems
Cell Signals and Apoptosis
Apoptosis(細胞凋亡)作用
真核細胞的死亡可由形態學及生化特性區分為細胞壞
死 (necrosis) 及細胞凋亡 (apoptosis)。與細胞壞死的被動過
程不同，細胞凋亡並不是病體條件下自體損傷的一種現象
，而是為維持內部穩定適應生存環境而主動採取的一種死
亡過 程。就像樹葉或花的自然凋落一樣 ，借用希臘詞
“apoptosis”來表示，可譯為“細胞凋亡”。
細胞凋亡作用發生時，細胞膜發生皺縮、 胞質濃縮、
染色質變得緻密，內源性核酸內切脢激活後，將染色體剪
切成單個或是寡核小體，這些核小體由histone與180 bp長
的DNA片段緊密結合所組成，在電泳圖上可看出階梯狀
的DNA-ladder。
Apoptosis Is Triggered by Death Signals
or Withdrawal of Survival Factors
• Two well-known death signals are received by
– Tumor necrosis factor receptor
– CD95/Fas receptor
• Cells require tropic, or survival factors to stay
alive
– Cytokines in bloodstream as survival factors
Cell signals and Programmed cell death
• Cells were infected by certain viruses, then
killer lymphocytes are activated and induce the
infected cells to initiate apoptosis
– Fas ligand (CD95 ligand) on the surface of
killer lymphocyte
– CD95/Fas receptor on the surface of the
target cells