Chapter 16 - cell communication

Cellular communication

involves converting those signals from one form to another

Cells communicate through a…

a large variety of extracellular signals

Signal Transduction

he process of converting an extracellular signal into an
intracellular signal to elicit a specific cellular response

Signaling Cell

produces a signal molecule that is detected by a target cell

Target Cells

have receptor proteins that recognize and respond to the signal
molecule

Signal transduction begins when…

when the receptor protein on the target cell receives an incoming extracellular signal and converts it to an intracellular signal

How do extracellular signal molecules stimulate a target cell?

By binding to its receptor proteins

Long-Range Signals and Communication

Endocrine and Synaptic/Neuronal

Short-Range Signals and Communication

Paracrine and Contact-Dependent

Endocrine communication

hormones are carried in the blood to distant target cells. “Public” communication

Synaptic/Neuronal Communication

transmitted along axons to remote target cells. Delivered through axons and neurons quickly and specifically

Paracrine Communication

signals released by cells into extracellular fluid and act locally. “Local mediator”

Autocrine signaling

local mediators that are produced by the cells themselves to
promote survival or proliferation. Used by cancer cells

Contact-Dependent Communication

direct communication through cell-cell contact

Neurotransmitters

Released when action potential hits a neuron cell. Electrical signal → chemical signal

Synaptic Gap

Gap between neuron cells that neurotransmitters cross

Cells of a multicellular organism are exposed to…

…hundreds of signals in its environment

The receptor protein determines if…

if a cell can respond to signals

The extracellular signal molecule alone is NOT…

…the message: the information conveyed by the signal depends on how the target cell receives and interprets the signal

Two categories of extracellular signals

1) Too large or too hydrophobic to cross the plasma membrane
2) Small enough or hydrophobic enough to diffuse across the membrane

Large and/or hydrophilic molecules:

must rely on membrane receptors to relay their message across the membrane

Small and/or hydrophobic molecules:

diffuse across the plasma membrane, and bind to intracellular enzymes

The receptor protein performs the 1 st signal transduction step

it binds the extracellular signal (primary messenger), and generates new intracellular signals (secondary messengers)

Molecular relay race

signals get passed “downstream” from one intracellular signaling molecule to the next, until the “response” Iof the cell has been completed

Intracellular signaling pathways perform one or more crucial functions:

1) relay the signal
2) amplify the signal
3) receive signals from multiple intracellular
signaling pathways and integrate them
4)distribute the signal

The “shape” of signal transduction pathways

Linear, branched, looped

Molecular switches function to allow signals to switch between…

..active and inactive states

Intracellular Signaling Proteins Can Act as…

Molecular Switches

Molecular Switches persists in the active state until

another switch turns them off

Proteins that act as molecular switches:

1) kinases
2) GTP-binding proteins

Three classes of cell-surface receptors

1) Ion-Channel-Coupled Receptors
2) G-Protein-Coupled Receptors (GPCRs): (Targets of ~ 50% known drugs)
3) Enzyme-Coupled Receptorsi

Ion Channel Coupled Receptors

Allows flow of ions across the plasma membrane, results in changes in the membrane potential and produces an electrical current

G-Protein-Coupled Receptors

Activates membrane-bound, trimeric GTP-binding proteins (G proteins), which then activate either an enzyme or an ion channel in the plasma membrane

GTP-Binding Proteins

Each is composed of a single polypeptide chain that is a seven-pass transmembrane receptor protein (spans the membrane 7 times)

When bound to a single molecule, the receptor protein undergoes a ____

conformational change

Each G protein is composed of…

α, β, and γ subunits

When does the a subunit have GDP bound?

in the unstimulated state

When does the a subunit release GDP in exchange for GTP?

When an extracellular ligand binds to the receptor

Enzyme-coupled receptors

are transmembrane proteins that display their ligand-binding domains on the outer surface of the plasma membrane

Cytoplasmic domain of the receptor

either acts as an enzyme itself or forms a complex with another protein that acts as an enzyme

What do enzyme-coupled receptors do?

• They respond to extracellular signal proteins (called growth factors) and regulate cell
  growth, proliferation, differentiation, and survival (typically slow response).

• Mediate reconfigurations of the cytoskeleton

• Abnormalities in these receptors are seen in cancer development

Receptor tyrosine kinases (RTKs)

contain a cytoplasmic domain that phosphorylates specific tyrosines on selected intracellular proteins

The binding of a signal molecule to a RTK results in the formation of a ….

DimerWh

What do RTKs activate?

They activate GTPase Ras

Ras

a small GTP-binding
protein that is bound by a lipid tail to the cytoplasmic face of the plasma membrane

Monomeric GTPases

A large family that contains Ras

About 30% of cancers contain…

activating mutations in Ras genes

Ras activates a…

…MAP-kinase signaling module

In its active state, Ras promotes the activation of a…

…a phosphorylation cascade, in which a series of serine/threonine protein kinases phosphorylate and activate one another

MAP-kinase signaling module

includes three-kinase proteins, in honor of the final
kinase in the chain, the
Mitogen-Activated Protein
kinase

Mitogens

are extracellular
signal molecules that stimulate
cell proliferation

PI-3-kinase-Akt signaling pathway

activated by RTKs.I

Insulin-like Growth Factor

activates an RTK, which recruits and activates PI 3-kinase

Phosphoinositide 3-kinase (PI 3-kinase)

then phosphorylates a membrane-associated inositol phospholipid, which
recruits a protein kinase called Akt that is activated by protein kinase 1 and 2.

Activated Akt promotes

it promotes cell survival

Akt (also called protein kinase B or PKB)

can promote cell growth and survival by
phosphorylating and inactivating the signaling protein called Bad

In its unphosphorylated state, Bad…

…indirectly promotes apoptosis (programmed cell death) by binding to and inhibiting Bcl2 (which otherwise suppresses apoptosis)Akt stimulates cells to grow in size by

Akt stimulates cells to grow in size by…

…activating Tor

Akt indirectly activates Tor by…

phosphorylating and inhibiting a protein that helps to keep Tor shut down

Tor (itself a serine/threonine kinase)

stimulates protein synthesis and inhibits protein degradation

The mutants shown here are
single tyrosines (Y1 or Y3)
that have been replaced by a
phenylalanine

As a result, the mutant
receptors no longer bind to
one of the intracellular
signaling proteins

A constitutively active form of Ras transmits…

…a signal even in the
absence of an extracellular signal molecule

A hypothetical Ras signaling pathway can be shut down by a…

a mutation in protein X

Adding a continuously active Ras to cells with a mutation in X…

restores activity to the pathway, allowing the signal to be transmitted even in the absence of an extracellular
signal molecule

The Notch receptor itself is a…

…a transcription regulator

When the membrane-bound signal protein Delta binds to its receptor, Notch, on a neighboring cell…

the receptor is cleaved. The released part of the cytosolic tail of Notch migrates to the nucleus, where it
activates Notch-responsive genes, such as genes that control nerve cell production in fruit fly

The binding of just a few chemical signals to a few receptors can result in…

…thousands of
activated intracellular proteins

Signals A, B, C, and D may activate different cascades of protein phosphorylation, each
of which…

…leads to the phosphorylation of the target protein

The target protein is activated on when these sites are phosphorylated and
therefore…

…active only when all signals are simultaneously present

Signals A and B could lead to the activation of kinase 1

which then phosphorylates
certain aa residues on the target protein

Signals B and D could then activate kinase 2

which then phosphorylates other aa
residues on the target protein, completing protein activation, and leading to the specific
cell response