Common Signalling Pathways

Question 1

What is cell signalling?

Answer 1

Communication between cells to govern basic cell activities and actions

Question 2

What happens in signal transduction?

Answer 2

cells convert one kind of signal or stimuli into another

Question 3

What are the 3 types of INTERCELLULAR SIGNALLING

Answer 3

• Autocrine signalling
• Paracrine signalling
• Endocrine signalling

Question 4

List the different molecular signalling pathways

Answer 4

• morphogens
• notch/delta
• transcription factors
• receptor tyrosine kinases (RTKs)

Question 5

What are the two proteins needed for intercellular communication?

Answer 5

• gap junctions (connexon)
• cell adhesion molecules (cadherin, immunoglobin super family)

Question 6

The anterior, posterior and anteroposterior axes of the embryo does what?

Answer 6

They determine the correct locations for things like the limbs and nervous system patterning

Question 7

What does excessive retinoic acid lead to

Answer 7

Because retinoic acid posteriorizes the body, when there’s excess, structures have a more posterior nature

Question 8

A more anteriorized body structure is caused by what?

Answer 8

• insufficient retinoic acid
• Defects in retinal aldehyde dehydrogenase (produces retinoic acid)

Question 9

Retinoic acid receptors are _________ and they __________ when activated. Their main targets are ______

Answer 9

• Transcription factors
• Regulate downstream gene expression
• Hox genes

Question 10

Explain the metabolic production of Retionic acid

Answer 10

Dietary vitamin A (retinol) is oxidized by retinol dehydrogenase which creates retinal. Retinal is oxidized by retinal aldehyde dehydrogenase creating the bio active form of ATRA (All Trans Retinoic Acid) all which cellular binding proteins are controlling their concentration.
Retinoic acid can be actively degraded into inactive metabolites by an enzyme (CYP26)

Question 11

What are the members of the TGF-ß superfamily and their function

Answer 11

• TGF-ß, BMPs, activin and nodal.
• Contribute to dorsoventral patterning, cell fate decisions and formation of specific organs

Question 12

What are morphogens?

Answer 12

• diffusible molecules that say where a cell is generated in the body and where they go till they get to their destination
• they can be expressed in opposing gradients (dorsal ventral etc)

Question 13

Name examples of morphogens

Answer 13

• Retinoic acid
• Transforming Growth Factor ß(TGF-ß)
• Sonic Hedgehog (patterns the ventral neural tube)
• Wnt proteins
• Bone Morphogenic Proteins (BMPs)

Question 14

The Wnt-secreted glycoproteins are vertebrate orthologs of _______

Answer 14

• The Drosophila gene Wingless

Question 15

What do Wnt proteins do?

Answer 15

• The control apoptosis, cell migration & cell fate specification

Question 16

Explain the Wnt/ß-catenin pathway when Wnt is present

Answer 16

• Wnt binds to Fzd (its receptor) with coreceptor LRP5/6
• Active Fzd phosphonylates DVL which is activated
• Active DVL binds to a complex to phosphorylate GSK3
• GSK3 with phosphor is inactive and cannot phosphorylate ß-catenin
• ß-catenin goes to nucleus and activates target genes with TCF (transcription factor)

Question 17

Explain the Wnt/ß-catenin pathway when Wnt is absent

Answer 17

• No Wnt to activate Fzd (cell surface receptor)
• No Fzd to phosphorylate DVL
• Inactive DVL cannot bind to protein complex
• GSK3 (a kinase) is active, (not phosphorylated) and it phosphorylates ß-catenin marking it for degradation
• No ß-catenin available to activate target genes

Question 18

What is different when Wnt is present versus absent

Answer 18

• When Wnt is present target genes in the nucleus are activated
• When Wnt is absent target genes in the nucleus are inactivated

Question 19

Sonic Hedgehog was the first mammalian ortholog of _______ to be identified

Answer 19

• The drosophila gene hedgehog

Question 20

What is different when Sonic Hedgehog is present versus absent

Answer 20

• In the presence of Shh, Gli becomes an activator (Gli-A) for target genes
• In the absence of Shh, Gli becomes a repressor (Gli-R) for target genes

Question 21

Explain the pathway of an absence Shh

Answer 21

• PTCH (shh receptor) inhibits smoothened (Smo) both transmembrane receptors
• Inactive Smo cannot act on Cos2 in a complex (Cos2, Fu, Gli)
• Another complex with activated GSK3 (kinase) phosphorylates Gli
• Phosphorylated Gli (Gli-R) is cleaved and goes into nucleus
• Gli-R represses target genes

Question 22

Explain the pathway of a present Shh

Answer 22

• Modified Shh ( post transcriptional addition of cholesterol to n-terminal) inhibits PTCH
• Smo is activated and acts on complex
• Complex conformation changes and Fu binds to SuFu (its suppressor)
• Gli is not phosphorylated and cleaved so it goes into nucleus as an activator
• Gli-A binds to CBP (transcription complex) which activates target genes

Question 23

How can an enzyme be switched ‘On’ or ‘off’

Answer 23

• By phosphorylation (kinases)
• by de-phosphorylation (phosphates)

Question 24

What is autocrine signalling?

Answer 24

• This is when the same cell that produces the ligand (signalling molecule) also produces the receptor
• This allows a cell to produce a signal for itself

Question 25

What is paracrine signalling?

Answer 25

- This is local signalling between cells - a cell produces the signalling molecules to bind & activate surrounding cells - enabled by diffusion

Question 26

What is endocrine signalling?

Answer 26

- This is the signal transfer in distant body sites - a signal is produced by a cell and transferred to a distal portion of the body through the bloodstream

Question 27

Explain the **active** TGF-ß/SMAD signalling pathway

Answer 27

- This pathway is active when TGF-ß binds to its type **II** receptor which an **inactive** kinase domain. The type **II** receptor transphosphorylates its type **I** receptor, activating the kinase domain - Then the type **I** receptor phosphorylates the receptor-associated SMAD protein (R-SMAD) - The R-SMAD protein binds to its common-partner (SMAD4) creating a complex that translocates to the nucleus - This complex then function as a transcription factor by directly binding to DNA which will **up-regulate** target genes

Question 28

Explain the gradient between Shh and BMP on the dorsoventral place of the neural tube

Answer 28

- The notochord and the floor plate of the neural tube secretes **high** levels of shh - The dorsoventral concentration of Shh is higher on the **floor plate** and lower on the **roof plate** (**ventral-to-dorsal**) - a member of the TGF-ß family (BMPs) is highly secreted on the roof plate in the opposing gradient of Shh (**dorsal-to-ventral**) - Together, they determine **dorsoventral cell fates**

Question 29

How many families of Wnt and Fzd are there?

Answer 29

- Wnt: 19 families - Fzd: 10 families

Question 30

What is the purpose of the notch/delta pathway

Answer 30

- To specify the fate of precursor cells - to maintain stem-cell niches - proliferation, apoptosis & differentiation

Question 31

Explain the notch/delta pathway

Answer 31

- This is a intercellular interaction - The delta/jagged ligand from one **differentiating** cell binds to the notch protein (receptor that's attached to NICD) on another **progenitor** cell - this binding event causes the **cleavage of NICD** from notch then it goes to the nucleus & binds to a TS complex, activating target genes (HES) which inhibits **differentiation in progenitor cells**

Question 32

Explain the role and function of transcription factors

Answer 32

- They are proteins that regulate gene expression by activation/repression - The bind to the promoter region sequences to regulate the rate of target gene transcription by interacting with accessory proteins

Question 33

What is the difference between a transcriptionally **active** and **inactive** chromatin

Answer 33

**ACTIVE** - transcription factors are able to bind - histone acetylases and kinases are activated to modify chromatin (histone activated) - histone deacetylases are inhibited **INACTIVE** - TFs can't bind - acetylases and kinases are inhibited - deacetylases are activated

Question 34

Examples of transcription factors

Answer 34

- HOX proteins (heart) - PAX genes (eyes) - basic helix-loop-helix TF (muscle)

Question 35

What is the purpose of receptor tyrosine kinases (RTKs)

Answer 35

They are essential for: - cell proliferation - apoptosis - migration - The growth of new blood vessels

Question 36

Name 5 abnormalities for Vitamin a (retinol)

Answer 36

- Spina Bifida - otosclerosis (the hardening of the ear) - Anophthalmia ( AACI the eyes) - Hypoplasia (insufficient formation or the lungs) - Spongy myocardium

Question 37

Name 3 abnormalities for Shh

Answer 37

- Holoproencephaly - Grig’s and Pallister Syndrome - Gorlin’s Syndrome

Question 38

Name 2 abnormalities for the Wnt/ß-Catenin pathway

Answer 38

- Williams-Beuren Syndrome - Osteoporosis-Pseudoglioma Syndrome

Question 39

Name 2 abnormalities for the Notch/Delta Pathway

Answer 39

- Alagile Syndrome - CADASIL

Question 40

Name 2 abnormalities for transcription factors

Answer 40

- Rubinstein-tayabi - Alpha-thalassemia/X-linked mental retardation

Question 41

Name 2 abnormalities for HOX proteins

Answer 41

- Cardiac atrial-septal defects - Lissencephaly Syndrome

Question 42

Name 3 abnormalities for PAX genes

Answer 42

- Occular defects - Alveolar rhabdomyosarcoma - Waardenburg’s Syndrome

Question 43

Name 2 abnormalities for RTKs

Answer 43

- Milroy disease - cancer

Question 44

what is the difference between a differentiating and a progenitor cell?

Answer 44

- in a differentiating cell, notch signalling is **inactive** - in a progenitor cell, the regulation of target genes, inhibits differentiation