Chapter 11: Cell Communication.

Why do cells need to signal? • Cells communicate with each other through cell-cell signaling.

• Signaling molecules are the chemical messengers used (sometimes called ligands)

Signal transduction pathways

•Are similar in microbes and mammals, suggesting an early origin –Suggests an evolutionary connection.

1 Exchange of ! factor mating factors. Receptor Each cell type secretes a mating factor a ! that binds to receptors on the other cell type. Yeast cell, a factor Yeast cell, mating type a mating type ! 2 Mating. Binding of the factors to receptors induces changes a ! in the cells that lead to their fusion. 3 New a/! cell. The nucleus of the fused cell a/ includes all the ! genes from the Figure 11.2 a and a cells. Signaling in multicellular organisms Long Distance Signaling • Can be both Local or Long-Distance •Endocrine: Signal is released into a carrier system, such as blood, which carries the molecules to the target cells, which can be far away. • Local Signaling – Examples of this are hormones. – Paracrine: The signaling molecule is released and diffuses Long-distance signaling to the neighboring cells. This is local Signaling. Endocrine cell Blood – Synaptic Signaling. Nerve cells signal across a synapse. vessel

Local signaling

Target cell Electrical signal along nerve cell triggers release of neurotransmitter Hormone travels in bloodstream to target cells Neurotransmitter Secretory diffuses across vesicle synapse Target cell

Local regulator diffuses through Target cell (c) Hormonal signaling. Specialized extracellular fluid is stimulated endocrine cells secrete hormones (a) Paracrine signaling. A secreting cell acts (b) Synaptic signaling. A nerve cell into body fluids, often the blood. on nearby target cells by discharging releases neurotransmitter molecules Hormones may reach virtually all molecules of a local regulator (a growth into a synapse, stimulating the Figure 11.5 C body cells. factor, for example) into the extracellular target cell. Figure 11.5 A B fluid. • For most signals the signaling molecule does not The signal-transduction pathway enter the cell • The response of the cell to a signaling molecule is mediated – The signal is relayed through the membrane, from the through a signal-transduction pathway. outside to the inside. • This occurs through 3 steps. – Reception • How is this done? – Transduction – Response

EXTRACELLULAR CYTOPLASM • The signaling molecule (ligand) binds to a FLUID Plasma membrane membrane receptor on the outside of the cell. 1 Reception 2 Transduction 3 Response • This receptor spans the membrane and has both Receptor an extracellular and a cytosolic domain. Activation of cellular response • The cytosolic domain changes shape when Relay molecules in a signal transduction pathway bound to ligand.

– The ligand is not always a diffusible molecule Signal molecule

Figure 11.6

Receptors G-Protein linked receptors • Are connected to a G-protein that is activated when a ligand binds to • There are three major types of membrane the receptor. • The activation triggers the displacement of the GDP by GTP. This receptors. activated G-protein then goes on to activate other proteins. • Example: Slime mold cAMP receptor system. – G-Protein linked receptors. Figure 11.7a – Tyrosine-Kinase Receptors – Ligand-gated Ion channels.

Focus on the G-Protein linked receptors Know the other pathways! Tyrosine-Kinase Receptors. Ligand-gated Ion channels • Form dimers. Signal Gate closed Ions • Phosphorylate the tyrosine amino acids on the other receptor molecule • This activates the receptor dimer (ligand) • Binding of ligand opens up an ion channel. • Example: Growth factor receptor.

Ligand-gated Plasma Signal Signal-binding sitea ion channel receptor Membrane molecule • The opening of the channel leads to a net flow of Signal !Helix in the molecule ions into or out of the cell. Membrane Gate open

Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr + 2+ Tyr Tyr Tyr Tyr • This triggers an intracellular response. Na , Ca Receptor tyrosine CYTOPLASM kinase proteins Dimer (inactive monomers) Cellular response Activated relay proteins Cellular P Tyr P Tyr Tyr P Tyr Tyr P Tyr response 1 Gate close Tyr Tyr PTyr Tyr P PTyr Tyr P Tyr P Tyr P Tyr Tyr P Cellular Tyr 6 ATP 6 ADP Tyr P response 2 Activated tyrosine- Fully activated receptor kinase regions tyrosine-kinase Inactive (unphosphorylated (phosphorylated relay proteins Figure 11.7 Figure 11.7 dimer) dimer)

Intracellular Receptors. Transduction The signal is relayed via cascades of molecular interactions in the cell. • Small non polar molecules, Hormones, can travel through the membrane where they can bind to an internal receptor protein • Amplification of the signal can be achieved by phosphorylation cascades • Usually activates a transcription factor. and second messengers • Adding or removing phosphate groups regulates protein activity.

Hormone EXTRACELLULAR • Kinases use ATP to phosphorylate molecules. (testosterone) FLUID 1 The steroid • Phosphatases remove phosphate groups from molecules. hormone testosterone passes through the plasma membrane. Signal molecule Plasma membrane Receptor 2 Testosterone binds protein to a receptor protein Receptor Activated relay Hormone- in the cytoplasm, molecule receptor activating it. Inactive complex protein kinase Active Phosphorylation 1 protein 3 The hormone- kinase receptor complex Inactive 1 enters the nucleus protein kinaseATP Active ADP P and binds to specific 2 protein PP kinase cascade DNA genes. Pi Inactive 2 mRNA 4 The bound protein protein kinaseATP Active ADP P stimulates the 3 protein transcription of PP kinase Pi 3 NUCLEUS New protein the gene into mRNA. Inactive ATP protein P 5 The mRNA is ADP Active Cellular translated into a PP protein response P i specific protein. Figure 11.6 CYTOPLASM Figure 11.9 Second messengers Nuclear response to a signal 2+ – cAMP and Ca or other small molecules (IP3, DAG) Regulate genes by activating transcription

1 A signal molecule binds 2 Phospholipase C cleaves a 3 DAG functions as factors that turn genes on or off to a receptor, leading to plasma membrane phospholipid a second messenger

activation of phospholipase C. called PIP2 into DAG and IP3. in other pathways. EXTRA- Growth factor Reception Signal molecule CELLULAR Receptor (first messenger) FLUID G protein

DAG

GTP Phosphorylation cascade Figure 11.13 G-protein-linked PIP2 Transduction receptor Phospholipase C IP3 (second messenger) CYTOPLASM

IP3-gated calcium channel

Inactive Endoplasmic Various transcription Active Cellular factor transcription reticulum (ER) Ca2+ proteins response Response activated factor P Ca2+ DNA (second messenger) Gene

4 IP quickly diffuses through 5 Calcium ions flow out of 6 The calcium ions 3 mRNA the cytosol and binds to an IP3– the ER (down their con- activate the next NUCLEUS gated calcium channel in the ER centration gradient), raising protein in one or more Figure 11.14 membrane, causing it to open. the Ca2+ level in the cytosol. signaling pathways.

The signaling is very specific Signal Transduction • Receptors only bind to a specific ligand.

Signal molecule EXTRA- Signal molecule CELLULAR • The same signaling molecule can lead to (first messenger) FLUID different responses in different types of Receptor G protein

cells. Relay DAG molecules GTP

– Example: Epinephrine G-protein-linked PIP2 Phospholipase C receptor IP Response 1 Response Response 3 – In liver it triggers breakdown of glycogen (second messenger) 2 – In the heart it increase the heart beat. 3 IP3-gated calcium channel

Endoplasmic Various Cellular reticulum (ER) Ca2+ proteins response activated Activation Ca2+ or inhibition (second messenger) Response 4 Response 5

Figure 11.17 Summary of signaling. Chapter 12 The Cell Cycle. Every living organism must be able to reproduce in • Via membrane proteins. order to survive. – G-Protein linked receptors. Many different G-proteins – Tyrosine-Kinase Receptors. • Reproduction occurs by Cell Division. – Ligand-gated Ion channels. – It is part of the Cell Cycle. – It results in genetically identical daughter cells • Directly Intracellular Receptors • The Cell Cycle is the foundation of life. – Non-polar molecules that bind to receptors inside cells. Usually activate transcription factors. • Unicellular organisms • Both can lead to amplification of signal. – Reproduce by cell division – Branching: Binding of signaling molecule can trigger several • Multicellular organisms depend on cell division for different responses inside cell. – Development from a fertilized cell – Combination of two different signals. – Growth – Repair

Genome Brief review

• The cells genetic information is called its genome. • Eukaryotic cell division consists of • The genome contains the recipe for running and building – Mitosis, the division of the nucleus the cell. – Cytokinesis, the division of the cytoplasm • The genome contains all the chromosomes. • The chromosome is made up of a very long linear DNA • In meiosis strand containing up to thousands of genes, each gene – Sex cells are produced after a reduction in specifying a specific protein. chromosome number • This strand is associated with various proteins that maintain the structure and control the activity of genes. • This DNA protein complex is called chromatin. – A cell can have 3 m long DNA strands even though it is only 10 !m long. The Cell Cycle is divided into Two Phases • DNA is Duplicated in S phase! Not in mitosis. • After the S phase each chromosome has an identical copy, the pair are Interphase and Mitosis (Mitotic phase) called sister chromatids. • They are joined at the Centeromere, a waist like region near the center of the chromosome. • Interphase is split into 3 phases • Kinetochores, where the microtubules attach, are formed here as well. • G1, S, G2 0.5 !m • After G2 the cell enters mitosis. A eukaryotic cell has multiple chromosomes, one of which is represented here. Before INTERPHASE duplication, each chromosome has a single DNA molecule. Chromosome duplication (including DNA synthesis) Once duplicated, a chromosome S consists of two sister chromatids Centromere G1 (DNA synthesis) connected at the centromere. Each chromatid contains a copy of the DNA molecule.

Sister G2 Separation chromatids Cytokinesis of sister MITOTIC Mitosis chromatids (M) PHASE Mechanical processes separate the sister chromatids into two chromosomes and distribute them to two daughter cells.

Figure 12.5 Figure 12.4 Centromeres Sister chromatids

Mitosis is split into five subphases It is made up of mitosis and cytokinesis • Prophase G OF – Two centerosomes already formed begin to move towards opposite poles of 2 PROPHASE PROMETAPHASE INTERPHASE Centrosomes the cell. Microtubules grow from the centerosomes. Chromosomes begin to Early mitoticAster Fragments (with centriole pairs) Chromatin Kinetochore spindle Centromere of nuclear condense and sister chromatid pairs become visible. (duplicated) envelope Nonkinetochore microtubules • Prometaphase – Nuclear envelope begins to break down. – Each of the two sister chromatids has now a structure called Kinetochore Kinetochore located at the centeromer region. Microtubules begin to attach to the Figure 12.6 Nucleolus Nuclear Plasma Chromosome, consisting microtubule kinetochores. envelopemembrane of two sister chromatids

• Metaphase – Centerosomes are at opposite poles. Chromosomes convene in the center between the two centerosomes .

METAPHASE ANAPHASE TELOPHASE AND CYTOKINESIS • Anaphase Metaphase plate Cleavage Nucleolus – The two sister chromatids are separated as the microtubules shorten. furrow forming

• Telophase – Two daughter nuclei form and the nuclear envelope arises from the fragments of the parents nuclear envelope. The chromosomes become less tightly Nuclear envelope Daughter coiled. Spindle Centrosome at forming Figure 12.6 one spindle polechromosomes Animal Mitosis (Bio Flix)

• Every Eukaryotic cell has a characteristic number of chromosomes. – Diploid cells have pairs of homologous chromosomes. – Haploid cells have single chromosomes. The only haploid cells in humans are the gametes.

Plant and animal Cytokinesis Bacteria divide by binary fission

• Cytokinesis, the division of the cytoplasm usually finishes at the end of telophase. Origin of Cell wall replication Plasma Membrane E. coli cell •In animal cells • In plant cells, during Bacterial Chromosome replication Two copies Chromosome –Cytokinesis occurs by a process cytokinesis 1 begins. of origin known as cleavage, forming a – A cell plate forms Soon thereafter, one copy of cleavage furrow the origin moves rapidly toward the other end of the cell. Replication continues. One copy of 2 Origin Origin the origin is now at each end of the cell.

3 Replication finishes. The plasma membrane grows inward, and Cleavage furrow 100 !m Vesicles Wall of 1 !m new cell wall is deposited. forming patent cell Cell plateNew cell wall cell plate

Figure 12.11 4 Two daughter cells result. Contractile ring of Daughter cells microfilaments Daughter cells Figure 12.9 A (a) Cleavage of an animal cell (SEM) Figure 12.9 B(b) Cell plate formation in a plant cell (SEM) How many chromatids does a human cell have after undergoing S-phase? Can the repeated cycle of cell divisions A) 46 continue unchecked?

B) 19

C) 23

D) 32

E) 92

Cell check points Cell cycle clock – Cyclins proteins whose concentrations cycles during the cell cycle • The cell cycle is regulated by a molecular control – Cyclin-dependent-Kinases (CDK’s) that are activated when bound to the system cyclins. – MPF maturation (mitotic) promotion factor at the G2 checkpoint, a cdk- • There are 3 major checkpoints during the cell cycle. cyclin complex.

G S G M G S G M – The G1 checkpoint goes into S or into G0 (a) Fluctuation of MPF activity and M 1 2 1 2 cyclin concentration during MPF activity the cell cycle – The G2 checkpoint Cyclin – And the Mitotic checkpoint. • Why are checkpoints necessary? Time

(b) Molecular mechanisms that 1 Synthesis of cyclin begins in late S help regulate the cell cycle phase and continues through G2. G1 checkpoint Because cyclin is protected from degradation during this stage, it accumulates. 5 During G1, conditions in the cell favor degradation of cyclin, and the Cdk G 1 S Control component of MPF is Cdk S system recycled. M Degraded G 2 G1 Cyclin G2 Cdk 2 Accumulated cyclin molecules checkpoint combine with recycled Cdk mol- G2 M Cyclin is ecules, producing enough molecules degraded Cyclin MPF of MPF to pass the G2 checkpoint and initiate the events of mitosis. M checkpoint Figure 12.14 G checkpoint 2 4 During anaphase, the cyclin component 3 MPF promotes mitosis by phosphorylating of MPF is degraded, terminating the M various proteins. MPF‘s activity peaks during Figure 12.17 A, B phase. The cell enters the G1 phase. metaphase. • Growth factors Control of Cell growth • PDGF ( Platelet derived growth factor) for fibroblasts affect the • Growth factors G checkpoint. 1 – PDGF ( Platelet derived growth factor) for fibroblasts affect the G1 • Density dependence and anchorage dependence inhibition. checkpoint. – Can lower density of growth factors. • Density dependence and anchorage dependence inhibition. – There is also contact inhibition. – Can lower density of growth factors. – There is also contact inhibition.

(a) Normal mammalian cells. The Cells anchor to dish surface and (a) Normal mammalian cells. The Cells anchor to dish surface and availability of nutrients, growth divide (anchorage dependence). availability of nutrients, growth divide (anchorage dependence). factors, and a substratum for factors, and a substratum for attachment limits cell attachment limits cell density to a single layer. When cells have formed a complete single layer, they density to a single layer. When cells have formed a complete single layer, they stop dividing stop dividing (density-dependent inhibition). (density-dependent inhibition).

If some cells are scraped away, the remaining cells If some cells are scraped away, the remaining cells divide to fill the gap and then stop (density-dependent divide to fill the gap and then stop (density-dependent inhibition). inhibition).

Figure 12.18 A Figure 12.19 A 25 !m 25 !m

Cancer

• Cancer cells – Exhibit neither density-dependent inhibition nor anchorage dependence – Have escaped from cell cycle control – Make excessive amounts of GF – Have lost the ability to be controlled by GF. – GF signaling pathway abnormal.

Tumor Lymph vessel

Blood vessel Glandular tissue Cancer cell Metastatic Tumor

Figure 12.20