Chapter 11 Cell Communication

I. Evolution of Cell Signaling Signal transduction pathway = steps by which a signal on a cell’s surface is converted into a cellular response Pathway similarities suggest signaling molecules evolved in prokaryotes and were modified later in eukaryotes

II. Local and Long-Distance Signaling Cells in a multicellular organism communicate by chemical messengers Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells Local signaling = animal cells may communicate by direct contact (cell-cell recognition)

Gap junctions between animal cells Plasmodesmata between plant cells Fig. 11-4 Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells (a) Cell junctions Figure 11.4 Communication by direct contact between cells (b) Cell-cell recognition

Animal cells also communicate using local regulators, messenger molecules that travel only short distances Long-distance signaling = plants and animals use hormones

(a) Paracrine signaling (b) Synaptic signaling Fig. 11-5ab 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 communication in animals Local regulator diffuses through extracellular fluid Target cell is stimulated (a) Paracrine signaling (b) Synaptic signaling

Long-distance signaling Fig. 11-5c Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream to target cells Figure 11.5 Local and long-distance cell communication in animals Target cell (c) Hormonal signaling

Cell Communication Intro (Andersen 10 min)

III. Three Stages of Cell Signaling Sutherland discovered how epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes: Reception Transduction Response

Plasma membrane 1 Reception Receptor Signaling molecule 1 Fig. 11-6-1 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 1 Reception Receptor Figure 11.6 Overview of cell signaling Signaling molecule

Plasma membrane 1 Reception Transduction Receptor Signaling molecule 1 Fig. 11-6-2 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathway Figure 11.6 Overview of cell signaling Signaling molecule

Plasma membrane 1 Reception Transduction Response Receptor Activation Fig. 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

IV. Reception Binding between a signal molecule (ligand) and receptor is highly specific Shape change in a receptor is often the initial transduction (sending) of the signal Most signal receptors are plasma membrane proteins

V. Receptors in Membrane Water-soluble signal molecules bind to receptor proteins in the plasma membrane G protein-coupled receptor is a plasma membrane receptor that works with the help of a G protein G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive

Signaling-molecule binding site Fig. 11-7a Signaling-molecule binding site Figure 11.7 Membrane receptors—G protein-coupled receptors, part 1 Segment that interacts with G proteins G protein-coupled receptor

Figure 11.7 Membrane receptors—G protein-coupled receptors, part 2 Fig. 11-7b Plasma membrane G protein-coupled receptor Inactive enzyme Activated receptor Signaling molecule GDP G protein (inactive) Enzyme GDP GTP CYTOPLASM 1 2 Activated enzyme Figure 11.7 Membrane receptors—G protein-coupled receptors, part 2 GTP GDP P i Cellular response 3 4

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

Fully activated receptor tyrosine kinase Fig. 11-7c Signaling molecule (ligand) Ligand-binding site Signaling molecule  Helix Tyr Tyr Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins Dimer CYTOPLASM 1 2 Activated relay proteins Figure 11.7 Membrane receptors—receptor tyrosine kinases Cellular response 1 Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Cellular response 2 Tyr Tyr P Tyr Tyr P Tyr P Tyr P 6 ATP 6 ADP Activated tyrosine kinase regions Fully activated receptor tyrosine kinase Inactive relay proteins 3 4

Ligand-gated ion channel receptor acts as a gate when the receptor changes shape Signal molecule binds as a ligand to the receptor, the gate allows ions, such as Na+ or Ca2+, through a channel in the receptor

1 Signaling molecule (ligand) Gate closed Ions Plasma membrane Fig. 11-7d 1 Signaling molecule (ligand) Gate closed Ions Plasma membrane Ligand-gated ion channel receptor 2 Gate open Cellular response Figure 11.7 Membrane receptors—ion channel receptors 3 Gate closed

VI. Intracellular Receptors Found in cytosol or nucleus of target cells Small / hydrophobic chemical messengers can cross membrane and activate receptors steroid and thyroid hormones of animals Activated hormone-receptor complex can act as a transcription factor, turning on specific genes

Hormone (testosterone) Plasma membrane Receptor protein DNA NUCLEUS Fig. 11-8-1 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-2 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-3 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-4 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor mRNA NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-5 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor mRNA NUCLEUS New protein CYTOPLASM

VII. Signal Transduction Pathways Mostly proteins relay a signal from receptor to response Receptor activates another protein, which activates another, and so on, until the protein producing the response is activated At each step, the signal is transduced into a different form, usually a shape change in a protein

VIII. Protein Phosphorylation&Dephosphorylation In many pathways, signal is transmitted by a cascade of protein phosphorylations Protein kinases transfer phosphates from ATP to protein Protein phosphatases remove the phosphates from proteins (dephosphorylation) The phos and dephos system acts as a switch, turning activities on and off

Phosphorylation cascade Fig. 11-9 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 Inactive protein kinase 3 Figure 11.9 A phosphorylation cascade ATP ADP Active protein kinase 3 P PP P i Inactive protein ATP ADP P Active protein Cellular response PP P i

IX. Second Messengers The extracellular signal molecule that binds to the receptor is a pathway’s “first messenger” Second messengers = small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases Cyclic AMP and calcium ions are common second messengers

A. Cyclic AMP Cyclic AMP (cAMP) = one of most widely used Adenylyl cyclase = enzyme in plasma memb, converts ATP to cAMP in response to an extracellular signal

Fig. 11-10 Figure 11.10 Cyclic AMP Adenylyl cyclase Phosphodiesterase Pyrophosphate P P i ATP cAMP AMP Figure 11.10 Cyclic AMP

Many signal molecules trigger formation of cAMP Other components of cAMP pathways are G proteins, G protein-coupled receptors, and protein kinases cAMP usually activates protein kinase A, which phosphorylates various other proteins Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase

First messenger Adenylyl cyclase G protein GTP G protein-coupled Fig. 11-11 First messenger Adenylyl cyclase G protein G protein-coupled receptor GTP ATP Second messenger cAMP Figure 11.11 cAMP as second messenger in a G-protein-signaling pathway Protein kinase A Cellular responses

B. Ca Ions and Inositol Triphosphate (IP3) Calcium (Ca2+) is an important second messenger because cells can regulate its concentration

EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion Fig. 11-12 EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) Figure 11.12 The maintenance of calcium ion concentrations in an animal cell Ca2+ pump ATP Key High [Ca2+] Low [Ca2+]

A signal relayed by a STP may trigger an inc in Ca in cytosol Pathways leading to the release of Ca involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers

EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein Fig. 11-13-1 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Ca2+ CYTOSOL

EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein Fig. 11-13-2 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Ca2+ Ca2+ (second messenger) CYTOSOL

EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein Fig. 11-13-3 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Various proteins activated Cellular responses Ca2+ Ca2+ (second messenger) CYTOSOL

Signal Transduction Pathways (Andersen 10min)

X. Nuclear and Cytoplasmic Responses Pathway leads to regulation of one or more cellular activities Pathways regulate the synthesis of enzymes / proteins, by turning genes on / off in nucleus Final molecule may function as a transcription factor

Growth factor Reception Receptor Phosphorylation cascade Transduction Fig. 11-14 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Figure 11.14 Nuclear responses to a signal: the activation of a specific gene by a growth factor Response P DNA Gene NUCLEUS mRNA

Other pathways regulate the activity of enzymes Reception Transduction Response Binding of epinephrine to G protein-coupled receptor (1 molecule) 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) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Glycogen Glucose-1-phosphate (108 molecules) Other pathways regulate the activity of enzymes

Signaling pathways can also affect the physical characteristics of a cell, for example, cell shape Directional Growth in Yeast RESULTS CONCLUSION Wild-type (shmoos) ∆Fus3 ∆formin Shmoo projection forming Formin P Actin subunit Fus3 Phosphory- lation cascade GTP G protein-coupled receptor Mating factor GDP Microfilament

XI. Fine-Tuning of the Response Multistep pathways have two important benefits:

A. Signal Amplification Enzyme cascades amplify the cell’s response At each step, the number of activated products is much greater than in the preceding step

B. Specificity and Coordination of the Response Different kinds of cells have different collections of proteins Allow cells to detect and respond to different signals Even the same signal can have different effects in cells with different proteins and pathways Pathway branching and “cross-talk” further help the cell coordinate incoming signals

Cell B. Pathway branches, leading to two responses. Fig. 11-17a Signaling molecule Receptor Relay molecules Figure 11.17 The specificity of cell signaling Response 1 Response 2 Response 3 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses.

Cell C. Cross-talk occurs between two pathways. Fig. 11-17b Activation or inhibition Figure 11.17 The specificity of cell signaling Response 4 Response 5 Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response.

C. Signaling Efficiency: Scaffolding Proteins Scaffolding proteins = large relay proteins to which other relay proteins are attached Can increase the signal transduction efficiency by grouping together different proteins involved in the same pathway

Signaling Plasma molecule membrane Receptor Three different protein Fig. 11-18 Signaling molecule Plasma membrane Receptor Three different protein kinases Figure 11.18 A scaffolding protein Scaffolding protein

D. Termination of the Signal When signal molecules leave the receptor, the receptor reverts to its inactive state

XII. Apoptosis (programmed cell death) Apoptosis is programmed or controlled cell suicide 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

Apoptosis of human white blood cells Fig. 11-19 Apoptosis of human white blood cells Figure 11.19 Apoptosis of human white blood cells 2 µm

Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Ced-4 Fig. 11-20a Ced-9 protein (active) inhibits Ced-4 activity Mitochondrion Figure 11.20 Molecular basis of apoptosis in C. elegans Ced-4 Ced-3 Receptor for death- signaling molecule Inactive proteins (a) No death signal

Ced-9 (inactive) Cell forms blebs Death- signaling molecule Active Fig. 11-20b Ced-9 (inactive) Cell forms blebs Death- signaling molecule Active Ced-4 Active Ced-3 Other proteases Nucleases Figure 11.20 Molecular basis of apoptosis in C. elegans Activation cascade (b) Death signal

XIII. Apoptotic Pathways and Signals 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 needed for the development and maintenance of all animals Apoptosis may be involved in some diseases (Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers

Effect of apoptosis during paw development in the mouse Fig. 11-21 Effect of apoptosis during paw development in the mouse Interdigital tissue 1 mm Figure 11.21 Effect of apoptosis during paw development in the mouse Overview Cell Communication (Bleier 17 min)