cell signaling i

A Simple Intracellular Signaling Pathway Activated by an Extracellular Signal Molecule

Figure 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015). 1

Characteristics of Extracellular Signaling Molecules Secreted from a signaling cell Peptides, amino acids nucleotides steroids retinoids, fatty acid derivatives, dissolved gases Released into extracellular space by exocytosis or diffusion

Characteristics of Receptor Proteins Target cell responds by means of a receptor Receptors are usually on the surface of the target cell (but can be found

inside the cell) Often a transmembrane protein Binds extracellular signal molecule with high affinity Upon binding the signaling molecule (ligand), the receptor *activates* a series of intracellular signals that alters cell behavior.

2

Forms of Intercellular Signaling

Extracellular signal molecules can act over either short or long distances Signaling and target cells are usually distinct cell types

Figure 15-2. Molecular Biology of the Cell 6e ( Garland Science, 2015). 3

The Binding of Extracellular Signal Molecules to Either Cell-Surface or Intracellular Receptors

(water soluble)

(Diffuses through lipid bilayer)

Most signal molecules are hydrophilic and unable to cross the plasma membrane of the target cell. They bind to cell surface receptors, which generate intracellular signals within the target.


Cells Depend on Multiple Extracellular Signals

Specific combinations of signaling molecules can regulate cell behavior

programmed

cell death


Figure 15-5. Molecular Biology of the Cell 6e (Garland Science, 2015).

Various Responses Induced by the Neurotransmitter Acetylcholine A B C D

Signal molecules differentially affect distinct target cells. The effect of a signal molecule on a cell is regulated by the intracellular molecules which respond to the receptor, downstream effector proteins and genes activated. These are dictated by the cells predetermined state which depends on the cells developmental history.

6

Three Classes of Cell-Surface Receptors

Protein lined channel through the membrane

receptor = channel protein

Receptor is a 7 pass transmembrane protein which activates a membrane bound (usually trimeric) GTPase (G-protein)

Single pass receptor is an enzyme or binds directly to an enzyme


A) Ion Channel-Coupled Receptors

B) G-Protein-Coupled Receptors

C) Enzyme-Coupled Receptors

7

Two Types of Intracellular Signaling Proteins That Act as Molecular Switches

-proteins activated or inactivated by phosphorylation

Kinase

(ser/thr

or tyr)

phosphatase

GTPase Intrinsic GTPase activity


-activated by GTP -monomeric trimeric

Cell Surface Receptors Relay Signals Via Intracellular Signaling Molecules

8

Three Types of Intracellular Signaling Complexes

Scaffold proteins serve as a strategy for enhancing specificity of interactions between signaling molecules by localizing them.

organize groups of interacting signaling proteins into signaling complexes

ensure they interact with each other and not with inappropriate partners.

increase local concentrations

speed

efficiency

decreases cross talk with other signaling pathways

A

B

C


Modular interaction domains mediate interactions between intracellular signaling proteins


activated insulin receptor

(insulin receptor substrate) -small interaction domains found in many signaling proteins -bind structural motifs found in other proteins and lipids

10

Molecular Interaction Domains Allow Assembly of Signal Complex

PTB - Phosphotyrosine binding SH2 - Src homology 2 binds phosphorylated tyrosine within a particular peptide sequence

SH3 - Src homology 3 binds proline-rich sequences

PH - Pleckstrin Homology - binds phosphoinositides to enable membrane docking

Adaptor - link proteins together through 2 or more interaction

Protein domains Chains or - signaling molecules assemble into complexes to Branching form chains and branching networks which cluster Networks in the lipid bilayer (rafts) of plasma membrane

11

Some Ways in Which Target Cells Can Become Adapted (Desensitized) to an Extracellular Signal Molecule

Adaptation of target cells to high levels of signaling proteins

Adjust sensitivity to signal

internalization internalization & degradation

in appropriate phosphorylation


Activation of a G protein by an activated GPCR


GPCRs large family of receptors which mediate cellular responses to extracellular signals -signal polypeptide chain which passes through the membrane 7 times -function through G-proteins to transmit signals -half of all known drugs work through GPCRs or their signaling pathways

Signaling through G-protein Coupled Receptors

ligand bound GPCR binds to and activates G-protein by triggering the exchange of GDP for GTP -GTP bound G-protein activates effector proteins such as the membrane-bound enzyme adenylate cyclase Adenylate cyclase Cyclic AMP (cAMP) GPCRs linked to a stimulatory G-protein (Gs) activate adenylate cyclase inhibitory G-protein (Gi) inhibit adenylate cyclase

13

The Synthesis and Degradation of Cyclic AMP


cAMP functions as a second messenger to activate cAMP-dependent enzymes in the cytosol, mainly cAMP dependent protein kinase A (PKA). PKA phosphoroylates ser-thr residues on target proteins

14

The Activation of Cyclic-AMP-Dependent Protein Kinase (PKA)


controls activity and subcellular localization

15


How a Rise in Intracellular Cyclic AMP Concentration Can Alter Gene Transcription

16

Table 15-1. Molecular Biology of the Cell 6e (Garland Science, 2015).

Some Hormone-Induced Cell Responses Mediated by Cyclic AMP

17

The Hydrolysis of PI(4,5) P2 by Phospholipase C-

Figure 15-28. Molecular Biology of the Cell 6e ( Garland Science, 2015).

G-protein Signaling Through Phospholipids

(DAG) DAG and Ca2+ are considered second messengers

18

How GPCRs Increase Cytosolic Ca2+ and Activate Protein Kinase C


Ca2+ is an effective signaling mediator because its cytosolic concentration is low (10-7M), whereas extracellular and lumen concentrations are high (10-3M). Ca2+ pumps in plasma and ER membranes drive Ca2+ out of the cell into the ER to lower cytosolic concentrations and terminate Ca2+ signaling.

19

The Structure of Ca2+/Calmodulin


Calmodulin is a Ca2+ binding protein which binds to and activates enzymes. Serves as a Ca2+ dependent regulatory subunit in many enzyme complexes. This family of enzymes is Ca2+/calmodulin-dependent kinases (CaM-kinases). They phosphorylate a variety of target proteins.

20

Some Cell Responses in Which GPCRs Activate PLC

Table 15-2. Molecular Biology of the Cell 6e (Garland Science, 2015). 21

Slide Number 1Slide Number 2Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21

A Simple Intracellular Signaling Pathway Activated by an Extracellular Signal Molecule


*

Characteristics of Extracellular Signaling MoleculesSecreted from a signaling cellPeptides, amino acids nucleotides steroids retinoids, fatty acid derivatives, dissolved gases

Released into extracellular space by exocytosis or diffusion

Characteristics of Receptor ProteinsTarget cell responds by means of a receptor

Receptors are usually on the surface of the target cell (but can be found inside the cell)

Often a transmembrane protein

Binds extracellular signal molecule with high affinity

Upon binding the signaling molecule (ligand), the receptor *activates* a series of intracellular signals that alters cell behavior.

*

Forms of Intercellular Signaling

Extracellular signal molecules can act over either short or long distancesSignaling and target cells are usually distinct cell types


*

The Binding of Extracellular Signal Molecules to Either Cell-Surface or Intracellular Receptors

(water soluble)

(Diffuses through lipid bilayer)

Most signal molecules are hydrophilic and unable to cross the plasma membrane of the target cell. They bind to cell surface receptors, which generate intracellular signals within the target.


*

Cells Depend on Multiple Extracellular Signals

Specific combinations of signaling molecules can regulate cell behavior


*


Various Responses Induced by the Neurotransmitter Acetylcholine

A

B

C

D

Signal molecules differentially affect distinct target cells. The effect of a signal molecule on a cell is regulated by the intracellular molecules which respond to the receptor, downstream effector proteins and genes activated. These are dictated by the cells predetermined state which depends on the cells developmental history.

*

Three Classes of Cell-Surface Receptors

Protein lined channel through the membrane receptor = channel protein

Receptor is a 7 passtransmembrane protein which activates a membrane bound (usually trimeric) GTPase (G-protein)

Single pass receptor is an enzyme or binds directly to an enzyme


A) Ion Channel-Coupled Receptors

B) G-Protein-Coupled Receptors

C) Enzyme-Coupled Receptors

*

Two Types of Intracellular Signaling Proteins That Act as Molecular Switches

-proteins activated or inactivated by phosphorylation

Kinase(ser/thr or tyr)

phosphatase

GTPase Intrinsic GTPase activity


-activated by GTP-monomeric trimeric

Cell Surface Receptors Relay Signals Via Intracellular Signaling Molecules

*

Three Types of Intracellular Signaling Complexes

Scaffold proteins serve as a strategy for enhancing specificity of interactions between signaling molecules by localizing them.organize groups of interacting signaling proteins into signaling complexesensure they interact with each other and not with inappropriate partners. increase local concentrations speed efficiency decreases cross talk with other signaling pathways

A

B

C


*

Modular interaction domains mediate interactionsbetween intracellular signaling proteins


activated insulin receptor

(insulin receptor substrate)

-small interaction domains found in many signaling proteins-bind structural motifs found in other proteins and lipids

*

Molecular Interaction Domains Allow Assembly of Signal Complex

PTB-Phosphotyrosine binding

SH2-Src homology 2 binds phosphorylated tyrosine within a particular peptide sequence

SH3-Src homology 3 binds proline-rich sequences

PH-Pleckstrin Homology - binds phosphoinositides toenable membrane docking

Adaptor-link proteins together through 2 or more interaction Proteindomains

Chains or -signaling molecules assemble into complexes to Branchingform chains and branching networks which cluster Networksin the lipid bilayer (rafts) of plasma membrane

*

Some Ways in Which Target Cells Can Become Adapted (Desensitized) to an Extracellular Signal Molecule

Adaptation of target cells to high levels of signaling proteins Adjust sensitivity to signal

internalization

internalization &degradation

in appropriate phosphorylation


*

Activation of a G protein by an activated GPCR


GPCRs

large family of receptors which mediate cellular responses to extracellular signals

-signal polypeptide chain which passes through the membrane 7 times

-function through G-proteins to transmit signals

-half of all known drugs work through GPCRs or their signaling pathways

Signaling through G-protein Coupled Receptors

*

The Synthesis and Degradation of Cyclic AMP


cAMP functions as a second messenger to activate cAMP-dependent enzymes in the cytosol, mainly cAMP dependent protein kinase A (PKA).

PKA phosphoroylates ser-thr residues on target proteins

*

The Activation of Cyclic-AMP-Dependent Protein Kinase (PKA)


controls activity and subcellular localization

*


How a Rise in Intracellular CyclicAMP Concentration Can Alter Gene Transcription

*


Some Hormone-Induced Cell Responses Mediated by Cyclic AMP

*

The Hydrolysis of PI(4,5) P2 by Phospholipase C-


G-protein Signaling Through Phospholipids

(DAG)

DAG and Ca2+ are considered second messengers

*

How GPCRs Increase Cytosolic Ca2+ and Activate Protein Kinase C


Ca2+ is an effective signaling mediator because its cytosolic concentration is low (10-7M), whereas extracellular and lumen concentrations are high (10-3M).

Ca2+ pumps in plasma and ER membranes drive Ca2+ out of the cell into the ER to lower cytosolic concentrations and terminate Ca2+ signaling.

*

The Structure of Ca2+/Calmodulin


Calmodulin is a Ca2+ binding protein whichbinds to and activates enzymes. Serves as a Ca2+ dependent regulatory subunit in many enzyme complexes. This family of enzymes is Ca2+/calmodulin-dependent kinases (CaM-kinases). They phosphorylate a variety of target proteins.

*

Some Cell Responses in Which GPCRs Activate PLC


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cell signaling i

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