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Terms
Contents adenylyl cyclase guanine nucleotide exchange
Terms autophosphorylation factor (GEF)
Introduction and Ca2+/calmoldulin-dependent inositol 1,4,5-triphosphate
Goals kinase (InsP3)
Cell Signaling calmodulin mitogen-activated protein (MAP)
Intracellular cAMP-dependent kinase (protein kinase
nuclear kinase A) nuclear receptor
receptors
cell signaling paracrine signaling
Extracellular
cyclic AMP (cAMP) phospholipase C
Receptors and
diacylglycerol Ras
Signal Transduction
endocrine signaling second messenger
Molecular Switches:
enzyme-linked receptor serine/threonine kinase receptor
Protein Kinases
extracellular receptor SH2 domain
and GTP-Binding
G-protein-linked receptor signal transduction
Proteins
G-Protein-Linked
GRB2 trimeric G-protein
Receptors GTP-binding protein (G-protein) tyrosine kinase receptor
The Cyclic AMP GTPase-activating protein (GAP)
Signaling Pathway
The Inositol
Phospholipid
Signaling Pathway
Enzyme-Linked Introduction and Goals
Receptors
This tutorial describes how cells communicate with each other. In a previous
SH2
tutorial you learned about a very specialized case of cell communication, neurons
domains
receiving and sending chemical signals. Now you will learn about some of the
Ras
more general mechanisms that cells use to receive and respond to signals.
signaling
Reception of a signal occurs through the binding of a signal molecule to a specific
Integration of
receptor; examples will be described and their mechanisms of action explained. In
Signaling Pathways
addition, you will learn how the binding of signal molecules to receptors triggers
Cell Signaling in
Plants intracellular changes in the receiving cell, affecting many cellular processes. You
Summary will learn how protein modification by phosphorylation and induced conformational
change by protein:protein interactions are used to mediate intracellular changes in
response to a signal.

By the end of this tutorial you should know:

the meaning of paracrine and endocrine signaling

the mechanism of intracellular nuclear receptors

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the mechanism of G-protein-linked receptors, and how they activate a G-

protein
how protein kinases and G-proteins act as molecular switches
the role of second messengers such as cAMP, InsP3 and calcium ions
the mechanism of tyrosine kinase receptors, and how they recruit and
activate multiple proteins
how the activity of Ras is regulated
the general difference between cell signaling in plants and animals

Cell Signaling
A hallmark of any multicellular organism is the ability of its cells to communicate
with each other. This communication, referred to as cell signaling, regulates
almost all cellular processes, including growth, metabolism, gene expression and
cytoskeletal organization. Cell signaling is the release of a signal molecule, a
chemical message, from one cell and the detection of this signal by another cell,
the target cell. The signal molecule is detected by the target cell through its
binding to a specific receptor. Once the receptor has bound the signal molecule, a
series of changes is initiated in the target cell that affects many cellular
processes. You have already learned about a rather specialized type of cell
signaling in the nervous system, chemical transmission at synapses that alter
membrane potential. We will now consider cell signaling that is more widespread
among many cell types. Cell signaling occurs in both animals and plants;
however, signaling in plants is not as well understood, so most of the material
presented in this tutorial relates to animal cells.

Signal molecules encompass a variety of molecules, including proteins, peptides

and small organic molecules. There are two distinct types of cell signaling:
paracrine signaling, which is mediated by signal molecules that are local
mediators and affect neighboring cells; and endocrine signaling, which is
mediated by signal molecules called hormones (secreted by specialized cells into
the bloodstream) and affect cells distributed throughout the organism. The
molecular mechanisms of paracrine and endocrine signaling are similar and
depend on the molecular structure of the signal itself. Most signal molecules are
extracellular and bind to receptors located in the plasma membrane of the target
cell. However, some are small lipid-soluble molecules that readily diffuse across
the plasma membrane of the target cell. Most notable of this type of signal
molecule are the steroid hormones estrogen and testosterone.

Intracellular nuclear receptors

Lipid-soluble hormones, such as the steroid
hormones, diffuse across the plasma membrane
and bind to intracellular receptors termed
nuclear receptors (illustrated in Figure 1).
Members of this family of receptors are
composed of two distinct domains, a ligand

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Figure 1. Nuclear binding domain and a transcription activation

receptors. domain. In the inactive state, many nuclear
receptors are located in the cytoplasm, bound to
inhibitor proteins. Once a lipid-soluble hormone
has entered the cell it binds to the receptor,
which is released from the inhibitor protein, and
the receptor/hormone complex enters the
nucleus. In the nucleus, the receptor/hormone
complex will bind to specific regions of DNA and
activate transcription of a subset of genes. The
expression of these genes is the primary
response of the cell to the hormone, however,
these genes encode a variety of proteins that will
affect many aspects of the cell's physiology.

Extracellular Receptors and Signal

Transduction
Many signal molecules are too large or insoluble to pass through the plasma
membrane. These signal molecules bind to specific cell surface, or extracellular,
receptors in the plasma membrane of target cells. Extracellular receptorsare
transmembrane proteins that have two distinct regions of activity, an extracellular
ligand-binding domain and an intracellular signaling domain. There are many
different members of this family of extracellular receptors, some of which will be
described in detail below; however, as a class, extracellular receptors function by
binding ligand on the outside of the cell and activating the receptor. Activation of
the receptor results in a conformational change in the intracellular portion of the
receptor, which, in turn, will recruit and activate a variety of intracellular proteins
that regulate many cellular processes. Thereby, the extracellular signal is
transmitted into the cell and affects change without actually entering the cell
through a process referred to as signal transduction. Unlike the nuclear
receptors that directly regulate transcription in the target cell, activated
extracellular receptors recruit and activate a variety of proteins in a signal
transduction pathway. Central to these signal transduction pathways are two
classes of protein, protein kinases and GTP-binding proteins, both of which act as
molecular switches to regulate the activity (either "on" or "off") of many other
proteins. So the binding of a ligand to a receptor on the outside of the cell triggers
receptor activation, which, in turn, recruits one or more intracellular molecular
switches, and these activate (or inactivate) a host of other proteins in the cell.
Ultimately this leads to changes in gene expression, metabolism and many other
cellular processes. The beauty of signal transduction pathways is that they are
very rapid, reversible and versatile, affecting many aspects of the cell's physiology
simultaneously. The remainder of this tutorial will describe several examples of
specific signal transduction pathways mediated by two distinct groups of
extracellular receptors: G-protein-linked receptors and enzyme-linked receptors.

Molecular Switches: Protein Kinases and

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GTP-Binding Proteins
Before we can discuss specific
signaling pathways, you need to
understand the activity and
regulation of protein kinases and
GTP-binding proteins. Protein
kinases are a class of enzymes that
phosphorylate other proteins; they
hydrolyze ATP to ADP and add a
Figure 2. Molecular switches: phosphate to specific amino acids
phosphorylation/dephosphorylation (see Enzyme Kinetics and Catalysis
and G-proteins. tutorial). Phosphorylation will alter
the conformation of the target
protein, and in some cases,
activate it, or in other cases,
inactivate it. Serine/threonine
protein kinases phosphorylate
those two residues, tyrosine protein
kinases phosphorylate the residue
tyrosine, and a few protein kinases
phosphorylate all three residues.
Phosphorylation is a reversible
modification of a protein, and there
are a large number of
phosphatases (enzymes that
remove phosphates from proteins
that are phosphorylated).
Therefore, the process of
phosphorylation/dephosphorylation
is a molecular switch;
phosphorylation by a specific
protein kinase activates (turns "on")
that protein, and dephosphorylation
by a specific phosphatase
inactivates (turns "off") that protein
(see Figure 2- panel A). Protein
kinases are an abundant and
diverse class of enzymes. It has
been estimated that in a typical
eukaryotic cell there are several
hundred different protein kinases,
and about one-third of the total
protein of the cell is
phosphorylated. All protein kinases
have a distinct subset of proteins
that they can phosphorylate,
however, some are more limited in
their substrates than others. Any
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given protein can be

phosphorylated by multiple kinases
at a variety of sites. All kinases are
regulated between the active and
inactive state through a variety of
mechanisms. Some kinases are
themselves activated by
phosphorylation, which initiates
signal transduction cascades of one
kinase activating another kinase,
which, in turn, activates yet another
kinase in the sequence, and so on.

GTP-binding proteins are another

class of molecular switches. All
GTP-binding proteins (G-proteins)
are characterized by their ability to
bind to and hydrolyze GTP, hence
their name. G-proteins are active
when bound to GTP but inactive
when bound to GDP (see Figure 2-
panel B). When active, G-proteins
can physically interact with and
activate (or in some cases,
inactivate) many other proteins.
When bound to GTP, G-proteins
remain active only briefly. The G-
protein rapidly hydrolyzes GTP to
GDP, then returns to its inactive
state. Although both protein kinase
and G-proteins hydrolyze
nucleotides (ATP and GTP,
respectively), recall, G-proteins do
not transfer a phosphate onto the
proteins they activate. A GTP-
bound G-protein activates its target
protein by physical interaction and
an induced conformational change.

G-Protein-Linked Receptors
The first signal transduction pathway that we will consider is triggered by G-
protein-linked receptors. G-protein-linked receptorsare the largest group in the
family of extracellular receptors found in animals, with as many as 2000 genes
encoding G-protein-linked receptors in the human genome. This diverse group of
receptors binds to a variety of signal molecules, including neurotransmitters (e.g.
acetylcholine) and hormones (e.g. adrenaline). The signaling pathways that they
initiate regulate cellular processes, including metabolism and transcription. Our
senses of sight and smell are mediated by G-protein-linked receptors. A large
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number of olfactory G-protein-linked receptors are located in specific neurons of

the nose. They bind odorant molecules and trigger a signaling pathway, which, in
turn, triggers a nerve impulse along the axons to the brain. Our ability to perceive
light is mediated by light-activated G-protein-linked receptors in the
photoreceptors of the eye.

Although quite diverse, members of this group of

ANIMATION(G-protein
linked receptor action)
extracellular receptors share some common
structural features. G-protein-linked receptors are
a single, transmembrane polypeptide threaded
through the lipid bilayer seven times (see
animation). There is an extracellular ligand-
binding domain and an intracellular domain that
interacts with and activates G-proteins. When the
receptor is activated by binding to the ligand on
the extracellular surface of the plasma
membrane, it undergoes a conformational
change. The activated receptor can now, in turn,
activate a trimeric G-protein.

Trimeric G-proteins are composed of three subunits (alpha, beta and gamma)
and are attached to the inner face of the plasma membrane through a covalent
lipid modification. In the inactive state, the alpha subunit is bound to GDP and
the three subunits form a complex. Upon ligand binding to the G-protein-linked
receptor, the receptor is activated to bind the G-protein and induce a
conformational change in the alpha subunit of the G-protein, so that GDP is
exchanged for GTP and the three subunits dissociate to release the GTP-alpha
subunit and the beta-gamma complex. The activated GTP-alpha subunit can
induce a conformational change in several target proteins, and, in turn, activate
(or inhibit) them. The alpha subunit also contains the GTPase activity, so it
remains active for a brief time period, but then it hydrolyses the GTP to GDP. The
GDP-bound alpha subunit reassociates with the beta-gamma complex and the
G-protein returns to its inactive state, ready to be activated once more in
response to ligand binding and receptor activation. There are several different
activating and inhibitory G-proteins in most animal cells, some with a specific
tissue distribution and others with a wide tissue distribution.

The Cyclic AMP Signaling Pathway

In many signaling pathways, including the
olfactory G-protein signaling pathways, G-
proteins stimulate production of cyclic AMP
(cAMP), a small intracellular molecule that
regulates many proteins in the cell. Cyclic AMP is
Figure 3. Mechanism synthesized from ATP by the enzyme adenylyl
of cAMP-dependent cyclase, which is a transmembrane protein. The
kinase. GTP-bound alpha subunit of an active trimeric
G-protein activates adenylyl cyclase, resulting in
a rapid increase in the intracellular levels of

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cAMP (see previous animation). Cyclic AMP is

referred to as a second messenger, with the first
messenger being the ligand that binds to and
activates the receptor.

A second messenger is characterized as a

small intracellular molecule that is an effector of
other proteins. In response to receptor activation,
there is a pronounced increase in the level of
second messengers, thus amplifying the signal
and transmitting it into the interior of the cell. G-
protein-linked receptors and trimeric G-proteins
are fixed at the plasma membrane; however, the
production of cAMP, which is small and
diffusable, allows the signal to be broadcast to
the interior of the cell, regulating the activity of
cytoplasmic and nuclear proteins. In addition, the
signal is amplified so that one molecule of ligand
binds to its receptor. This activates several
molecules of trimeric G-protein, which, in turn,
activate adenylyl cyclase to synthesize many
molecules of cAMP. Thus, one molecule of ligand
binding to its receptor results in hundreds to
thousands of molecules of cAMP becoming
available in the cell.

In some neurons, including the olfactory neurons, cAMP regulates cAMP-gated

ion channels to trigger an axon potential and a nerve impulse. In many other cells,
however, the primary role of cAMP is allosteric regulation of the serine/threonine
protein kinase cAMP-dependent kinase (protein kinase A). In its inactive state,
cAMP-dependent kinase is composed of four subunits: two catalytic subunits that
encode kinase activity and two regulatory subunits that inhibit kinase activity.
Cyclic AMP binds to the regulatory subunits and alters their conformation, which
causes them to dissociate from the complex and release the catalytic subunits
(Figure 3). Active cAMP-dependent kinase can phosphorylate and regulate a
variety of proteins. In muscle cells, cAMP-dependent kinase phosphorylates and
activates the enzymes involved in glycogen breakdown and simultaneously
inactivates the enzymes involved in glycogen synthesis. In other cells, cAMP-
dependent kinase phosphorylates and regulates a DNA binding protein that
regulates the transcription of a subset of genes.

The Inositol Phospholipid Signaling

Pathway
Not all signaling pathways initiated by G-protein-
linked receptors activate adenylyl cyclase and
employ cAMP as a second messenger. In some
signaling pathways, the trimeric G-proteins
activate another transmembrane protein,
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phospholipase C. This enzyme cleaves a lipid

found on the inner surface of the lipid bilayer,
phosphatidylinositol 4,5-biphosphate, to generate
two products: diacylglycerol and inositol 1,4,5-
triphosphate (InsP3) (Figure 4). Diacylglycerol
remains associated with the plasma membrane,
Figure 4.
and activates the serine/threonine protein kinase
Phospholipase C and
known as protein kinase C. Activation of protein
inositol signaling.
kinase C also requires calcium (see below), and
once the kinase is active, it will phosphorylate
and regulate a variety of different proteins,
including other kinases.

The second cleavage product, InsP3, is a small,

water-soluble molecule that rapidly diffuses
through the cytoplasm. When it reaches the

Figure 5. Ca++/ endoplasmic reticulum, InsP3 binds to InsP3-

Calmodulin regulation. gated Ca2+ channels in the ER membrane. The

lumen of the smooth ER has a large store of
calcium ions, and when the InsP3-gated Ca2+
channels are open, there is a large influx of
calcium ions into the cytoplasm, raising the
calcium concentration by 10- to 20-fold. Calcium
ions act as second messengers. Protein kinase C
binds to calcium, and both calcium and
diacylglycerol are required for the activation of
this kinase. However, many of the effects of
intracellular calcium ions are mediated by
calcium-binding proteins. The most common of
these is^ calmodulin, which is active when it is bound to
calcium. Calmodulin has no enzymatic activity. It functions

by binding to and activating other enzymes (see Figure 5).

Calmodulin also has indirect effects by activating

serine/threonine protein kinases, the family of

Ca2+/calmodulin-dependent kinases. These

kinases have a broad specificity and mediate
many of the effects of calcium in animal cells.

Enzyme-Linked Receptors
The predominant type of enzyme-linked
receptors found in animals is the family of the
tyrosine kinase receptors, also referred to as
receptor tyrosine kinases (illustrated in Figure 6).
These receptors have intrinsic kinase activity
Figure 6. Tyrosine encoded by the intracellular domain, also referred
kinase receptors. to as the cytoplasmic tail. Tyrosine kinase
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receptors bind extracellular ligands as a dimer (a

pair of identical proteins). Once ligand is bound,
the receptors are activated and the cytoplasmic
kinase domains are brought into close proximity
where they can cross-phosphorylate on multiple
tyrosines. The process by which one molecule of
the receptor dimer phosphorylates its partner is
referred to as autophosphorylation.

SH2 domains
How does autophosphorylation broadcast the signal to the interior of the cell?
Once the cytoplasmic tails of tyrosine kinase receptors are phosphorylated, they
act as docking sites that recruit and activate many different types of signaling
molecules, including a form of phospholipase C, protein kinases and G-proteins.
Although the recruited proteins are not similar in overall structure or function, they
all share the ability to directly, or indirectly, bind to the phosphorylated tyrosines of
the activated receptors via a shared protein domain. A distinct, relatively short
protein motif termed the SH2 domain, found in many unrelated signaling
molecules, encodes the phosphotyrosine binding activity. Therefore, proteins that
contain SH2 domains will be recruited to the activated tyrosine kinase receptors
via binding to the phosphotyrosines, and, in turn, will be activated either by
phosphorylation or simply by binding. For instance, phospholipase C is recruited
to the activated receptors by the binding of its SH2 domian to the
phosphotyrosines of the receptors. Upon binding, it is activated to generate
diacylglycerol and InsP3and to trigger the inositol phospholipid signaling pathway.
An activated pair of tyrosine kinase receptors can recruit many different proteins
simultaneously, each protein binding to a specific phosphotyrosine in the
cytoplasmic tails of the receptors.

Ras signaling
Among the proteins that are commonly recruited
to activate tyrosine kinase receptors is the G-
protein Ras. Ras is a member of a large family of
monomeric (single subunit) G-proteins. Ras has
a covalently attached lipid group and is
associated with the intracellular face of the lipid
bilayer. Similar to trimeric G-proteins, Ras is
Figure 7. Regulation
active when bound to GTP and inactive when
of Ras activity
bound to GDP. It is also a GTPase and it
hydrolyzes GTP to inactivate itself. There is
reciprocal regulation of Ras GTPase activity by
GTPase-activating proteins (GAPs) that
promote hydrolysis of GTP, and guanine
nucleotide exchange factors (GEFs) that
promote the exchange of GDP for GTP (see

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Figure 8. Ras signaling Figure 7). Ras is recruited to the activated

and MAP kinase tyrosine kinase receptors indirectly through its
pathway association with a particular GEF known as SOS.
SOS also does not bind phosphotyrosines, and is
itself recruited to activated tyrosine kinase
receptors via a small adapter protein known as
GRB2, which contains an SH2 domain and can
bind phosphotyrosine. To recapitulate, activated
tyrosine kinase receptors recruit the adapter
protein GRB2 via its SH2 domain that binds
phosphotyrosines, and GRB2 is bound to SOS.
Once SOS is recruited to the receptor complex, it
can activate Ras by promoting the release of
GDP and the binding of GTP. Ras-GTP will
activate a variety of proteins by induced
conformational change. Ultimately, activated Ras
leads to changes in the pattern of gene
expression. This effect is largely mediated by
Ras activation of a protein kinase pathway
referred to as the mitogen-activated protein
(MAP) kinasepathway. Ras activates a kinase,
which, in turn, phosphorylates and activates
another kinase that activates the last kinase is
this cascade (see Figure 8). MAP kinase is the
last in the cascade, and when it is activated by
phosphorylation, it will phosphorylate a number of
nuclear proteins that regulate transcription.

Integration of Signaling Pathways

You have learned about several signaling pathways involving G-protein-linked
receptors or enzyme-linked receptors, however, there are many more signaling
pathways that have not been discussed herein. Signal transduction is a rapidly
growing field of biology, and new signaling pathways are revealed regularly.
Unfortunately there is not enough time to explore all of the different signaling
pathways in an introductory course. This tutorial presents a few examples that are
well-established paradigms for how cells integrate and respond to extracellular
signals.

Although each pathway has been presented as distinct and separate, this is not
true in a cell. Any given animal cell responds to multiple signals simultaneously.
Some signals trigger G-protein-linked receptor pathways, and others trigger
enzyme-linked receptor pathways. There is also cross talk between pathways. For
example, recall that phospholipase C and the inositol phospholipid signaling
pathway can be activated via G-protein-linked receptors and tyrosine kinase
receptors.

Sometimes distinct signals can act synergistically to reinforce the same changes
in a cell, whereas other times they can act antagonistically and have opposing

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effects in a cell. For instance, a cell may receive two signals that both induce
proliferation, or one signal that is proliferative and the other a cue to stop dividing.
Signals can also result in different outcomes in different cell types, depending on
the receptors and other signaling molecules expressed in the cell. In fact, there is
a whole network of signaling pathways in cells that run parallel, that intersect, and
that act either synergistically or antagonistically.

Cell Signaling in Plants

The signaling pathways that have been described so far are specific for animal
cells. Plant cells are capable of cell signaling and do employ signal transduction
pathways, although they appear to be quite distinct. Also, signaling pathways in
plants have not been as extensively studied as those in animals and until recently
have been poorly understood. The recent determination of the genomes of
several plant species has expanded our knowledge of the type of signaling
molecules plants possess. There are no known intracellular nuclear receptors in
plants. There are a few putative G-protein-linked receptors and a relatively small
number of trimeric G-proteins, but it remains unclear if cAMP is involved in
signaling pathways in plants. The predominant type of receptor in plants is the
enzyme-linked receptor, specifically the serine/threonine kinase receptors. This
type of receptor binds to ligands and has intrinsic serine/threonine kinase activity.
Mechanistically, they function in a manner similar to the tyrosine kinase receptors
in animals, although the proteins and their specific interactions are distinct. In
plants, the serine/threonine kinase receptors autophosphorylate and recruit a
variety of signaling proteins via binding to phosphoserine or phosphothreonine,
whereupon they are phosphorylated and activated. Interestingly, there do not
appear to be any tyrosine kinase receptors or Ras monomeric G-proteins in
plants. However, there is good evidence for the MAP kinase signaling pathway.

Summary
Cells communicate through the actions of chemical signals. These can be locally
acting paracrine signals or globally acting endocrine signals that circulate in the
bloodstream and affect cells far from the source. The signal itself can be a
protein, peptide or small organic molecule. All signals bind to a specific receptor
and trigger a set of intracellular events that alter the state of the cell. Lipid-soluble
signals, such as the sex hormones, pass directly through the plasma membrane
and bind to intracellular nuclear receptors that are in an inactive state in the
cytoplasm. When the hormone binds to the receptor, the complex enters the
nucleus and directly binds to DNA to regulate gene expression. Extracellular
signals are more common. These molecules cannot enter the cell by passive
diffusion; instead, they bind to receptors on the cell surface. Once the
extracellular receptor is bound, it is activated and will recruit and activate a variety
of proteins, resulting in a signal transduction pathway.

Two distinct groups of extracellular receptors that are common in animals are G-
protein-linked receptors and enzyme-linked receptors. G-protein-linked receptors
bind extracellular ligand (a messenger) and activate an intracellular trimeric G-

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protein by stimulating the alpha subunit to bind GTP, in favor of GDP, and
dissociate from the beta-gamma subunits. The GTP-bound alpha subunit is
active for a period of time and then hydrolyzes the GTP to return to the inactive
GDP-bound state. During the period that the G-protein is active, it will trigger the
release of second messengers through a variety of mechanisms. Some G-
proteins activate adenylyl cyclase to synthesize cAMP. cAMP, in turn, activates
the cAMP-dependent kinases. Other G-proteins stimulate phospholipase C, an
enzyme that generates InsP3 and diacylglycerol. Diaclyglycerol and calcium
activate protein kinase C. InsP3 triggers the opening of InsP3-gated calcium
channels in the ER and results in a rapid influx of calcium ions. Calcium ions have
multiple effects in a cell. Many of these are mediated by the calcium-binding
protein calmodulin, which, in turn, activates other proteins (including the
Ca^+2^/calmodulin-dependent kinases).

Tyrosine kinase receptors bind ligand as a dimer and undergo

autophosphorylation of specific tyrosines in the cytoplasmic tails of the proteins.
Once phosphorylated, the receptor complex recruits a variety of different signaling
molecules. Recruitment is mediated by binding to the phosphotyrosines via a
conserved protein domain, the SH2 domain, within the signaling molecules, or
within adapter proteins associated with the signaling molecules. Among the
proteins recruited to an activated tyrosine kinase receptor is the G-protein Ras.
Ras is recruited and activated by the guanine exchange factor SOS, which is itself
recruited to the activated receptor by the adapter protein GRB2. Once RAS is
delivered to the activated receptor complex, it will activate the MAP kinase
cascade, resulting in active MAP kinase that will phosphorylate a variety of
transcription factors.

Plants have distinct signaling pathways that share some common features with
the signaling pathways in animals. The predominant type of receptor in plants is
the serine/threonine kinase receptor. These receptors undergo
autophosphorylation when active and recruit other proteins via binding to
phosphoserines and phosphothreonines.

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