Fig Chapter 11 Cell Communication

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Concept 11.1: External signals are converted to responses within the cell Microbes are a window on the role of cell signaling in the evolution of life A signal transduction pathway converts signals on a cell ’ s surface into cellular responses Yeast cell, mating type a Yeast cell, mating type  New a/  cell Fig. 11-2

Fig Local signaling Target cell Secreting cell Secretory vesicle Local regulator diffuses through extracellular fluid (a) Paracrine signaling(b) Synaptic signaling Target cell is stimulated Neurotransmitter diffuses across synapse Electrical signal along nerve cell triggers release of neurotransmitter Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream to target cells Target cell (c) Hormonal signaling Local and Long-Distance Signaling

The Three Stages of Cell Signaling: Earl W. Sutherland discovered how the hormone epinephrine acts on cells Earl W. Sutherland, Jr. –The Nobel Foundation. Sutherland suggested that cells receiving signals went through three processes: –Reception –Transduction –Response

Fig Reception 1 EXTRACELLULAR FLUID Receptor Signaling molecule Plasma membrane CYTOPLASM 1

Fig Reception 1 EXTRACELLULAR FLUID Receptor Signaling molecule Plasma membrane CYTOPLASM 1 Relay molecules in a signal transduction pathway Transduction 2

Fig EXTRACELLULAR FLUID Plasma membrane CYTOPLASM Receptor Signaling molecule Relay molecules in a signal transduction pathway Activation of cellular response Reception TransductionResponse 1 2 3

Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane There are three main types of membrane receptors: –G protein-coupled receptors –Receptor tyrosine kinases –Ion channel receptors

Fig. 11-7a Signaling-molecule binding site Segment that interacts with G proteins G protein-coupled receptor

Fig. 11-7b G protein-coupled receptor Plasma membrane Enzyme G protein (inactive) GDP CYTOPLASM Activated enzyme GTP Cellular response GDP P i Activated receptor GDP GTP Signaling molecule Inactive enzyme

Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once

Fig. 11-7c Signaling molecule (ligand) Ligand-binding site  Helix Tyrosines Tyr Receptor tyrosine kinase proteins CYTOPLASM Signaling molecule Tyr Dimer Activated relay proteins Tyr P P P P P P Cellular response 1 Cellular response 2 Inactive relay proteins Activated tyrosine kinase regions Fully activated receptor tyrosine kinase 6 6 ADP ATP Tyr P P P P P P

A ligand-gated ion channel receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na + or Ca 2+, through a channel in the receptor

Fig. 11-7d Signaling molecule (ligand) Gate closed Ions Ligand-gated ion channel receptor Plasma membrane Gate open Cellular response Gate closed 3 2 1

Intracellular Receptors found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers Examples : the steroid and thyroid hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes

Fig Hormone (testosterone) Receptor protein Plasma membrane EXTRACELLULAR FLUID DNA NUCLEUS CYTOPLASM

Fig Receptor protein Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM

Fig Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM

Fig Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM

Fig Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein Plasma membrane Hormone- receptor complex DNA mRNA NUCLEUS New protein CYTOPLASM

Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell involves multiple steps amplify a signal: A few molecules can produce a large cellular response provide more opportunities for coordination and regulation of the cellular response

23 Phosphorylation is key in control of protein function Addition of phosphate group A cell’s response to a signal often involves activating or inactivating proteins Phosphorylation is a common way to change the activity of a protein –Protein kinase – an enzyme that adds a phosphate to a protein –Phosphatase – an enzyme that removes a phosphate from a protein This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

Fig Signaling molecule Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP ADP Active protein kinase 2 P P PP Inactive protein kinase 3 ATP ADP Active protein kinase 3 P P PP i ATP ADP P Active protein PP P i Inactive protein Cellular response Phosphorylation cascade i  usually involves multiple steps  can amplify a signal  usually a shape change  by a cascade of protein phosphorylations  provide coordination and regulation of the cellular response

Second Messengers The extracellular signal molecule : “ first messenger ” Second messengers are small, nonprotein, water-soluble molecules or ions participate in pathways initiated by G protein- coupled receptors and receptor tyrosine kinases Cyclic AMP and calcium ions are common second messengers

Adenylyl cyclase Fig Pyrophosphate P P i ATP cAMP Phosphodiesterase AMP Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal

First messenger Fig G protein Adenylyl cyclase GTP ATP cAMP Second messenger Protein kinase A G protein-coupled receptor Cellular responses

EXTRACELLULAR FLUID Fig ATP Nucleus Mitochondrion Ca 2+ pump Plasma membrane CYTOSOL Ca 2+ pump Endoplasmic reticulum (ER) Ca 2+ pump ATP Key High [Ca 2+ ] Low [Ca 2+ ] Calcium Ions and Inositol Triphosphate (IP3)

Nuclear and Cytoplasmic Responses Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities The response may occur in the cytoplasm or may involve action in the nucleus Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus The final activated molecule may function as a transcription factor

Fig EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein GTP G protein-coupled receptor Phospholipase C PIP 2 IP 3 DAG (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) Ca 2+ CYTOSOL

Fig G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C PIP 2 DAG IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) Ca 2+ CYTOSOL Ca 2+ (second messenger ) GTP

Fig G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C PIP 2 DAG IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) Ca 2+ CYTOSOL Various proteins activated Cellular responses Ca 2+ (second messenger ) GTP

33 Adenylyl cyclase

Phosphatidylinositol 4,5-bisphosphate

Fig Growth factor Receptor Phosphorylation cascade Reception Transduction Active transcription factor Response P Inactive transcription factor CYTOPLASM DNA NUCLEUS mRNA Gene

Fig Reception Transduction Response Binding of epinephrine to G protein-coupled receptor (1 molecule) Inactive G protein Active G protein (10 2 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (10 2 ) ATP Cyclic AMP (10 4 ) Inactive protein kinase A Active protein kinase A (10 4 ) Inactive phosphorylase kinase Active phosphorylase kinase (10 5 ) Inactive glycogen phosphorylase Active glycogen phosphorylase (10 6 ) Glycogen Glucose-1-phosphate (10 8 molecules)

37

Fig a RESULTS Wild-type (shmoos) ∆Fus3 ∆formin How do signals induce directional cell growth in yeast?

Fig b CONCLUSION Mating factor G protein-coupled receptor GDP GTP Phosphory- lation cascade Shmoo projection forming Fus3 Formin P P P P Actin subunit Microfilament

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

Fig a Signaling molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses. Response 2 Response 3

Fig b Response 4Response 5 Activation or inhibition Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Scaffolding proteins are large relay proteins to which other relay proteins are attached Scaffolding proteins can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway

Fig Signaling molecule Receptor Scaffolding protein Plasma membrane Three different protein kinases

Fig. 11-UN1 Reception Transduction Response Receptor Relay molecules Signaling molecule Activation of cellular response 1 2 3

Concept 11.5: Apoptosis (programmed cell death) integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide A cell is chopped and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells

Fig µm

Apoptosis in the Soil Worm Caenorhabditis elegans Apoptosis is important in shaping an organism during embryonic development The role of apoptosis in embryonic development was first studied in Caenorhabditis elegans In C. elegans, apoptosis results when specific proteins that “ accelerate ” apoptosis override those that “ put the brakes ” on apoptosis

Fig Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Receptor for death- signaling molecule Ced-4 Ced-3 Inactive proteins (a) No death signal Ced-9 (inactive) Cell forms blebs Death- signaling molecule Other proteases Active Ced-4 Active Ced-3 Nucleases Activation cascade (b) Death signal

Fig a Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-4Ced-3 Receptor for death- signaling molecule Inactive proteins (a) No death signal

Fig b (b) Death signal Death- signaling molecule Ced-9 (inactive) Cell forms blebs Active Ced-4 Active Ced-3 Activation cascade Other proteases Nucleases

Apoptotic Pathways and the Signals That Trigger Them Caspases are the main proteases (enzymes that cut up proteins) that carry out apoptosis Apoptosis can be triggered by: –An extracellular death-signaling ligand –DNA damage in the nucleus –Protein misfolding in the endoplasmic reticulum

Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals Apoptosis may be involved in some diseases (for example, Parkinson ’ s and Alzheimer ’ s); interference with apoptosis may contribute to some cancers Fig Interdigital tissue 1 mm

You should now be able to: 1.Describe the nature of a ligand-receptor interaction and state how such interactions initiate a signal-transduction system 2.Compare and contrast G protein-coupled receptors, tyrosine kinase receptors, and ligand-gated ion channels 3.List two advantages of a multistep pathway in the transduction stage of cell signaling 4.Explain how an original signal molecule can produce a cellular response when it may not even enter the target cell 5.Define the term second messenger; briefly describe the role of these molecules in signaling pathways 6.Explain why different types of cells may respond differently to the same signal molecule 7.Describe the role of apoptosis in normal development and degenerative disease in vertebrates