Week 7 Cell communication

Question 1

Signal transduction pathways

Answer 1

convert extracellular signals into cellular responses

Question 2

2 types of cell communication:

Answer 2

1. Local signaling: neighbouring cells communicate though cell junctions, cell-to-cell recognition or local regulators
2. Long distance signaling: distant cells in multicellular organisms communicate using chemical messengers (e.g. hormones)

Question 3

In local signaling, cells may communicate by (3):

Answer 3

– Direct contact: via cell junctions (animal and plant cells); directly connect the cytoplasm of adjacent cells => coordinate the function of neighbouring cells in a tissue

– Cell-cell recognition: via surface molecules (animal cells only); communicate and recognize each other via direct contact using surface molecules (e.g. membrane carbohydrates)

– Local regulators: in paracrine/synaptic signaling (animal cells only) - messenger molecules that travel only short distances (e.g. growth factors, neurotransmitters)

Question 4

Local signaling: communication by local regulators mechanisms described:

Answer 4

Paracrine signaling: A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) into the extracellular fluid.

Synaptic signaling: A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell. (Electrical signal along nerve cell triggers release of neurotransmitter => Neurotransmitter diffuses across synapse => Target cell is stimulated)

Question 5

Cell junction types: cell-to-cell connection

Communicating junctions (2):

Answer 5

• Gap junctions: in animal cells, no cytoskeletal connection
• Plasmodesmata: in plant cells, no cytoskeletal connection

Connect cytoplasm of neighboring cells directly

Question 6

Cell junction types: cell-to-cell connection

Occluding junctions (1):

Answer 6

Tight junctions: connect with actin microfilaments

Question 7

Cell junction types: cell-to-cell connection

Anchoring junctions (2) and connect w/:

Answer 7

• Desmosomes: connect with intermediate filaments
• Adherens junctions: connect with actin microfilaments

Question 8

Gap junctions: communicating junctions (structure, exchange - ?, function, location, examples)

Answer 8

Structure: Cytoplasmic channels made by membrane proteins (connexins) connecting adjacent cells; necessary for cell-to-cell communication

Exchange: small molecule and ion exchange b/w cells (e.g. cAMP, Ca+2)

Function: Cell communication

Location: Located along the apical surfaces of cells of various tissues (e.g. epithelial cells and heart muscle)

Examples: Transport of Ca+2 b/w neighbouring smooth muscle cells through gap junctions => Synchronized contraction of intestine and uterus during birth

Question 9

Tight junctions: communicating junctions (structure, exchange - ?, function, location)

Answer 9

Structure: Made by 2 types of transmembrane proteins - claudin and occludin; the cytoplasmic part of occludin is linked to the actin microfilaments

Exchange: NO. Create an exclusion zone around the cells => prevent leakage of extracellular fluid from a layer of epithelial cells (e.g skin layer)

Function: Inhibit cell-to-cell communication (molecule exchange)

Location: Underneath the apical surface of epithelial cells

Question 10

Anchoring junction types (2 groups with 2 types in each):

Answer 10

• Connect neighbouring cells (Cell-to-cell connection):
- Desmosomes
- Adherens junctions

• Connect cells with ECM (Cell to ECM connection):
- Focal adhesions
- Hemidesmosomes

Question 11

Desmosomes (function, cytoskeletal connection, intercellular connection, clinical correlation)

Answer 11

• Fn: fasten cells together into strong sheets
• Anchor to the cytoplasm through intermediate filaments (e.g. keratin in epithelial cells, desmin in heart muscle cells & smooth muscle cells)
• Connect cells via transmembrane adhesion proteins (cadherins)
• Clinical correlation. Desmosomes attach muscle cells to each other in a muscle => Some ‘muscle tears’ involve the rupture of desmosomes

Question 12

Desmosomes: structure picture

Answer 12

transmembrane adhesion protein (cadherin) in extracellular space connects to intermediate filaments inside the cell through an attachment protein

Question 13

Adherens junctions (fn, cytoskeletal connection, intercellular connection)

Answer 13

• Fn: create adhesion zone (belt) underneath the apical surface of epithelial cells
• Intracellular attachment proteins (catenins, vinculin, α-actinin): connect cadherins with actin microfilaments
• Connect the plasma membranes of neighbouring cells via transmembrane adhesion proteins (cadherins)

Question 14

Adherens junctions vs desmosomes

Answer 14

Similar except for cytoskeletal connection (Actin microfilaments for Adherence junctions and Intermediate filaments for Desmosomes)

Question 15

Focal adhesions / Focal contacts (cytoskeletal connection, ECM (extracellular) connection):

Answer 15

• Intracellular connection: Integrin cytoplasmic domain connects with actin microfilaments through attachment proteins (talin, α-actinin, vincoulin)
• Extracellular connection: Connect cells to the ECM through integrins (transmembrane proteins), which bind to glycoprotein in ECM

Question 16

Hemidesmosomes (cytoskeletal connection, ECM (extracellular) connection, location):

Answer 16

• Intracellular connection: connect with keratin intermediate filaments through attachment proteins (plectin)
• Extracellular connection: Stabilise epithelial cells by anchoring them to the ECM through integrins (transmembrane proteins; integrin binds to basement membrane laminin)
• Found mainly in basal surface of epithelial cells

Question 17

Anchoring junctions summary: Desmosomes (cell-cell)

Transmembrane linker protein -
Extracellular ligand -
Intracellular Cytoskeletal Attachment -

Answer 17

Transmembrane linker protein - cadherin (desmogleins & desmocollins)
Extracellular ligand - cadherin in neighboring cell
Intracellular Cytoskeletal Attachment - intermediate filaments

Question 18

Anchoring junctions summary: Adherens junctions (cell-cell)

Transmembrane linker protein -
Extracellular ligand -
Intracellular Cytoskeletal Attachment -

Answer 18

Transmembrane linker protein - cadherin (E-cadherin)
Extracellular ligand - cadherin in neighboring cell
Intracellular Cytoskeletal Attachment - actin filaments

Question 19

Anchoring junctions summary: Focal adhesions (cell-EM)

Transmembrane linker protein -
Extracellular ligand -
Intracellular Cytoskeletal Attachment -

Answer 19

Transmembrane linker protein - integrin
Extracellular ligand - EM proteins
Intracellular Cytoskeletal Attachment - actin filaments

Question 20

Anchoring junctions summary: Hemidesmosomes (cell-EM)

Transmembrane linker protein -
Extracellular ligand -
Intracellular Cytoskeletal Attachment -

Answer 20

Transmembrane linker protein - integrin (α6,β4)
Extracellular ligand - basal lamina proteins
Intracellular Cytoskeletal Attachment - intermediate filaments

Question 21

Summary of animal cell junctions: functions

Tight junction:

Answer 21

seals neighboring cells together in an epithelial sheet to prevent leakage of molecules b/w them

Question 22

Summary of animal cell junctions: functions

Adherens junction:

Answer 22

joins an actin bundle in one cell to a similar bundle in a neighboring cell

Question 23

Summary of animal cell junctions: functions

Desmosome

Answer 23

joins the intermediate filaments in one cell to those in a neighboring cell

Question 24

Summary of animal cell junctions: functions

Gap junction

Answer 24

allows passage of small water-soluble ions and molecules

Question 25

Summary of animal cell junctions: functions Hemidesmosome

Answer 25

anchors intermediate filaments in a cell to the basal lamina

Question 26

Summary of animal cell junctions: functions Focal adhesions:

Answer 26

Anchors actin microfilaments to the basal lamina (ECM type)

Question 27

The Three Stages of Cell Signaling

Answer 27

1. Reception 2. Transduction 3. Response

Question 28

Reception -

Answer 28

the signaling molecule (**ligand**) binds to a receptor protein, causing conformational change, which then initiates the process of transduction

Question 29

conformational change -

Answer 29

change of shape of a receptor protein due to ligand binding

Question 30

Receptor types (2):

Answer 30

- Plasma membrane receptors (majority) - Intracellular receptors (minority)

Question 31

Intracellular receptors - 2 types and what signaling molecules use them? Examples Clinical correlation

Answer 31

1. cytoplasmic proteins 2. nuclear proteins Signaling molecules that are small or hydrophobic and can readily cross the plasma membrane use these receptors Ex: *steroid hormones*: estrogens (e.g. estradiol) and androgens (e.g. testosterone) bind to *intracellular steroid receptors*: Estrogen receptors (ERs) and androgen receptors (ARs) Clinical correlation: **tamoxifen** - drug used for treatment of ER+ breast cancer (ER+: expresses the estrogen receptors like normal tissue which is better prognosis than ER- b/c the latter is less differentiated, loss its expression, more invasive) Mode of action of tamoxifen: **Estrogen antagonist (binds to the ER and prevents estradiol binding)**

Question 32

three main types of plasma membrane receptors:

Answer 32

– G-protein-coupled – Tyrosine kinases – Ion channels

Question 33

G protein-coupled receptors -

Answer 33

plasma membrane receptors linked to a G protein

Question 34

G-proteins - what are they and clinical correlation (2)

Answer 34

proteins bound to GTP/GDP, act as an on/off switch: – If **GDP** is bound to the G protein => G protein is **inactive** – If **GTP** is bound to the G protein => G protein is **active** => hydrolysis can inactivate them Clinical correlation: 1. Involved in many human diseases, including bacterial infections: *cholera toxin* and *botulinum toxin* are bacterial products that interfere with G protein function 2. More than 60% of all medicines used today exert their effects by influencing G protein pathways

Question 35

Protein kinases -

Answer 35

enzymes that phosphorylates protein substrates (add phosphate groups to them)

Question 36

Receptor tyrosine kinases: definition, structure, examples, mode of action

Answer 36

transmembrane receptors that attach phosphates to tyrosine residues 3 domains: *Extracellular* ligand binding domain, *Transmembrane* domain, *Intracellular* domain with tyrosine kinase activity Ex: Growth factor receptors are commonly receptor tyrosine kinases (e.g. *EGFR* (epidermal growth factor receptor), *PDGFR* (platelet derived growth factor receptor)) Growth factor binding to their receptor tyrosine kinases => Activation of signal transduction pathways such as the **MAPK pathway** (MAPK - Mitogen Activated Protein Kinase) => DNA polymerase production for further cell division

Question 37

Receptor tyrosine kinases scheme:

Answer 37

Ligand binding => **receptor dimerization** => **Autophosphorylation** of tyrosine residues => activation => Phosphorylation of other proteins => Activation of signal transduction pathways (e.g. MAPK pathway)

Question 38

Receptor tyrosine kinases: clinical correlations

Answer 38

Abnormal tyrosine kinase receptors may contribute to some kinds of cancer: truncated receptors that function in the absence of signaling molecules (lack the ligand-binding domain) => overexpression/ amplification of receptors => overproduction of protein. Ex: **EGFR** (Epidermal Growth Factor Receptor) amplification (overexpression) in many cancers (e.g. breast cancer - HER2+) Several anti-cancer drugs block tyrosine kinase activity: **herceptin** - monoclonal antibody that competes w/ EGF in EGFR **Gleevec** - blocks enzymatic activity of the receptor => it can’t go into phosphorylation => activation of transduction is blocked

Question 39

Transduction -

Answer 39

signal from the receptor converted to a form that can cause a specific cellular response, usually requires a series of changes in a series of different target molecules

Question 40

Signal transduction pathways -

Answer 40

cascades of molecular interactions that relay signals from receptors to target molecules in the cell; at each step in a pathway the signal is transduced into a different form (usually a conformational change in a protein)

Question 41

Protein Phosphorylation and Dephosphorylation: participants of the process

Answer 41

– **Protein kinases**: enzymes that add a phosphate to the next protein kinase in line => **activate** protein kinases – **Phosphatases**: enzymes that remove the phosphates => **deactivate** the protein kinases

Question 42

Second messengers -

Answer 42

small, non-protein, water-soluble molecules or ions that act in the signal transduction pathways (after the action of *first messenger* - ligand) *cAMP, Ca+2, IP3, DAG*

Question 43

Cyclic AMP (cAMP):

Answer 43

Produced from **ATP** through the enzyme **adenylyl cyclase** which takes out 2 phosphate groups Many G-proteins trigger the formation of cAMP, it then acts as a second messenger in the signal transduction pathways

Question 44

Inositol Triphosphate (IP3) and Diacylglycerol (DAG):

Answer 44

IP3 triggers an **increase** in Ca2+ concentration in the cytosol Activated G protein activates phospholipase C => Phospholipase C cleaves a plasma membrane phospholipid called PIP2 (twice phosphorylated phosphatidilinositol) into **DAG** and **IP3** => DAG causes variety of cell responses, IP3 goes to IP3-gated Ca2+ channels in smooth ER => Ca2+ goes into cytosol (facilitated diffusion)

Question 45

Response (2 types) -

Answer 45

transduced signal triggers a specific cellular response: regulation of cytoplasmic activities (**cytoplasmic response**) or transcription (**nuclear response**)

Question 46

Example of Cytoplasmic response to a signal -

Answer 46

Glycogen breakdown into glucose

Question 47

Example of Nuclear response to a signal -

Answer 47

steroid hormone signaling pathways, MAPK signaling cascade

Question 48

Basement membrane (basal lamina) -

Answer 48

specialized ECM type that separates an endothelial cell layer form the underlying connective tissue

Question 49

Connective tissue -

Answer 49

consists mostly of ECM secreted by the fibroblasts

Question 50

Cyclic AMP signal transduction pathway:

Answer 50

Many G-proteins trigger formation of cAMP => cAMP acts as a second messenger in the signal transduction pathways **First messenger** (*ex: epinephrine*) binds to **G-protein- linked receptor** + GTP => Adenylyl cyclase => ATP - cAMP (**second messenger**) => Protein kinase A =>>> cellular responses