Cell Signaling

Pathways with friends helps understand…

Learning Targets I can summarize what is occurring in the three stages of cell communication:  reception, transduction and response. I can describe how the following receive cell signals and start transduction: G-protein coupled receptors tyrosine kinase receptors ion channels I can identify and describe the role of second messengers such as cyclic AMP and Ca2+ I can describe how a cell signal is amplified by a phosphorylation cascade. I can describe how a cellular response in the nucleus differs from a cellular response in the cytoplasm. I can explain what apoptosis means and why it is important for normal functioning of multicellular organisms.

Focus Questions Why do cells need to communicate? Explain what happens during the three phases of signal transduction. What is the purpose of second messengers? Diagram the epinephrine signaling pathway.  Diagram signal reception, transduction and response. Define each of the following phenomena, identify the organisms that they occur in, and explain how cellular signaling is used in each of them: a. Quorum Sensing b.  Apoptosis  Why do you think cellular signaling pathways and mechanisms are so universal among life’s domains? What are the similarities and differences in G-Protein, Tyrosine Kinase, and ligant-gated ion channel signaling pathways? How does a signaling pathway lead to an amplification of the response to the signal?  How can a signaling pathway have multiple physiological effects on a cell or organism?

Neurotransmitter diffuses across synapse. Secreting cell Figure 11.5a Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Secreting cell Secretory vesicle Figure 11.5 Local and long-distance cell signaling by secreted molecules in animals. Local regulator diffuses through extracellular fluid. Target cell is stimulated. (a) Paracrine signaling (b) Synaptic signaling

Different Ligands have different receptors

EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception Receptor Figure 11.6-1 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception Receptor Figure 11.6 Overview of cell signaling. Signaling molecule

Relay molecules in a signal transduction pathway Figure 11.6-2 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathway Figure 11.6 Overview of cell signaling. Signaling molecule

Relay molecules in a signal transduction pathway Figure 11.6-3 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Figure 11.6 Overview of cell signaling. Signaling molecule

G protein-coupled receptor Plasma membrane Activated receptor Figure 11.7b G protein-coupled receptor Plasma membrane Activated receptor Signaling molecule Inactive enzyme GTP GDP GDP CYTOPLASM G protein (inactive) Enzyme GTP 1 2 GDP Activated enzyme Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors GTP GDP P i 3 Cellular response 4

Signaling molecule (ligand) Ligand-binding site Figure 11.7c Signaling molecule (ligand) Ligand-binding site  helix in the membrane Signaling molecule Tyr Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr CYTOPLASM Receptor tyrosine kinase proteins (inactive monomers) Dimer 1 2 Activated relay proteins Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors Cellular response 1 Tyr Tyr P Tyr P Tyr P Tyr Tyr P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Cellular response 2 Tyr Tyr P Tyr Tyr P Tyr Tyr P 6 ATP 6 ADP P Activated tyrosine kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine kinase (phosphorylated dimer) Inactive relay proteins 3 4

Signaling molecule (ligand) Figure 11.7d 1 2 3 Gate closed Ions Gate open Gate closed Signaling molecule (ligand) Plasma membrane Ligand-gated ion channel receptor Cellular response Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-1 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-2 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-3 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-4 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. mRNA NUCLEUS CYTOPLASM

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-5 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. mRNA NUCLEUS New protein CYTOPLASM

Activated relay molecule Figure 11.10 Signaling molecule Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP Phosphorylation cascade ADP Active protein kinase 2 P PP P i Figure 11.10 A phosphorylation cascade. Inactive protein kinase 3 ATP ADP Active protein kinase 3 P PP P i Inactive protein ATP ADP P Active protein Cellular response PP P i

Glucose 1-phosphate (108 molecules) Figure 11.16 Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Figure 11.16 Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine. Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose 1-phosphate (108 molecules)

Inactive transcription factor Active transcription factor Figure 11.15 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Figure 11.15 Nuclear responses to a signal: the activation of a specific gene by a growth factor. Response P DNA Gene NUCLEUS mRNA

Wild type (with shmoos) Fus3 formin CONCLUSION Figure 11.17 RESULTS Wild type (with shmoos) Fus3 formin CONCLUSION 1 Mating factor activates receptor. Mating factor Shmoo projection forming G protein-coupled receptor Formin P Fus3 Actin subunit GTP P GDP 2 Phosphory- lation cascade G protein binds GTP and becomes activated. Formin Formin Figure 11.17 INQUIRY: How do signals induce directional cell growth during mating in yeast? P 4 Fus3 phos- phorylates formin, activating it. Microfilament Fus3 Fus3 P 5 Formin initiates growth of microfilaments that form the shmoo projections. 3 Phosphorylation cascade activates Fus3, which moves to plasma membrane.

Activation or inhibition Figure 11.18 Signaling molecule Receptor Relay molecules Activation or inhibition Figure 11.18 The specificity of cell signaling. Response 1 Response 2 Response 3 Response 4 Response 5 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses. Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

Why does epinephrine have 2 very different responses?

APOPTOSIS Ced-9 protein (active) inhibits Ced-4 activity Figure 11.21 APOPTOSIS Ced-9 protein (active) inhibits Ced-4 activity Ced-9 (inactive) Cell forms blebs Death- signaling molecule Mitochondrion Active Ced-4 Active Ced-3 Other proteases Ced-4 Ced-3 Nucleases Receptor for death- signaling molecule Activation cascade Figure 11.21 Molecular basis of apoptosis in C. elegans. Inactive proteins (a) No death signal (b) Death signal

Cells undergoing apoptosis Figure 11.22 Cells undergoing apoptosis Space between digits 1 mm Interdigital tissue Figure 11.22 Effect of apoptosis during paw development in the mouse.

DRAW IT A DEATH SIGNAL IS RECEIVED WHEN A MOLECULE CALLED FAS BINDS ITS CELL-SURFACE RECEPTOR. THE BINDING OF MANY FAS MOLECULES TO RECEPTORS CAUSES RECEPTOR CLUSTERING. THE INTRACELLULAR REGIONS OF THE RECEPTORS, WHEN TOGETHER BIND PROTEINS CALLED ADAPTOR PROTEINS. THESE, IN TURN, BIND TO INACTIVE MOLECULES OF CAPASE-8, WHICH BECOME ACTIVATED ACTIVE CAPASE-8 THEN ACTIVATED CAPASE-3. ACTIVE CAPASE-3 INITIATES APOPTOSIS

Figure 11.UN02 Figure 11.UN02

2012 Nobel Prize Awarded for work on G Coupled Protein Receptors Brian Kobilka Robert Lefkowitz