Lectures: 13-20 Flashcards
What can initiate a signal transduction?
They can be initiated by receptors that contain protein kinases as apart of their structure.
Examples are: Insulin signaling pathway and EGF signaling pathway
What is a dimer?
When two molecules interact with each other
How does the Insulin signaling pathway work?
- Insulin receptor is a dimer of two identical units (one alpha, one beta)
- Each unit contains a protein kinase domain
- insulin receptor is activated because tyrosine kinase becomes auto-phosphorylated on tyrosine OH
How is insulin signaling terminated?
it is terminated by the action of phosphatases
What are the three classes of phosphatases that help terminate Insulin signaling?
- Protein tyrosine - remove phosphoryl groups from insulin receptor
- Lipid phosphatases - remove the phosphoryl groups from inositol lipids (PIP3 to PIP2)
- Protein serine - remove phosphoryl group from activated protein kinases
How is the EGF signaling pathway terminated?
- Phosphatases remove phosphoryl groups from tyrosine residues on EGF receptor, then they form serine, threonine, and tyrosine residues in protein kinases.
- Which participate in signaling a cascade
What is a protein kinase?
An enzyme that is capable of transferring a phosphate group on an acceptor amino acid in a protein substrate
What can happen if there are defects in cell signaling?
- This is when cancer can occur, cancer is characterized by uncontrolled cell growth
-Ras gene is one of the most commonly mutated genes in human cancer - Ras can be trapped in the ‘on’ position and then continues to stimulate cell growth.
What is Gleevec (STI571)?
It is a targeted anti-cancer drug
Which cancers most commonly have over-expressed EGFR?
- Breast, ovarian and colorectal cancer.
- Amplification of Her-2 (25% if cancer patients)
- cell growth
What is a notch signaling pathway?
- Highly conserved pathway across species
- regulates cellular identity, proliferation, differentiation and apoptosis in animals
What is apoptosis?
The death of cells - normal
What are key players in the basic Notch pathway?
- Delta-type ligand
- Receptor notch
- Proteases
- CSL transcription factor
How is the Notch signal pathway activated?
- notch receptor undergoes proteolytic processing in the Golgi
- transported to cell surface membrane
- Notch-ECD ‘receiving’ cells bind with notch ligands, expressed by the ‘sending’ cell
- induces the 2nd proteolytic step, S2 cleavage by ADAM metalloproteases, leads to endocytosis
How is Notch signaling switched off?
- Once the target genes have been expressed Notch-ICS is downregulated
- ubiquitin ligase attaches multiple ubiquitin molecules to Notch-ICD targeting it to the proteasome
- proteasome degrades proteins marked by ubiquitin
-SHUT the PATHWAY DOWN
Why have there been efforts to create Notch inhibitors?
Because it could be helpful to treat cancer, there are two major classes y-secretase and monoclonal antibodies
How do organisms respond to nutrient fluctuations?
organisms respond by altering the balance between energy-producing catabolic processes and energy-consuming anabolic processes.
What does TOR kinase do?
It regulates several cellular processes (e.g. translation, transcription) in response to nutritional status and signals from cell surface receptors
What are TORC1 and TORC2?
They are mammalian cells that are made apart of mTOR along with Raptor
What does mTOR1 control?
It controls protein synthesis by phosphorylating kinase S6K1/2 and 4EBP1 (increase in protein synthesis)
What does S6K1/2 (kinase) do?
phosphorylates ribosomal proteins, leading to an increase in the rate of protein synthesis.
What does 4E-BP1 do?
inhibits interaction of key translation initiation factor - inhibits protein synthesis, stimulates translation initiation
How is mTOR activity regulated?
- it is regulated by the G-protein Rheb
What is found in plants for nutrient signaling?
Conserved TORC1 complex (TOR, raptor, LST8)
How are AMPKs activated?
They are activated by a decrease i energy level, sensed by an increase in the AMP/ATP ratio, or by nutrient starvation
What is development?
A highly coordinated series of events
What are model organisms (examples too)?
The organisms that researchers use to study development.
e.g. Drosophila, xenopus, Arabidopsis (just a few examples)
- Mice, chicken, nematode worm also used !
What are some reasons for model organisms?
- Quick life-span or reproduction
- genome sequenced
- accessible
- A lot known about them
- easy to manipulate
(just a few)
What are the steps of embryology? (5 steps)
- fertilization
- cleavage
- Gastrulation
- neurulation
- organogenesis
What is Gastrulation?
It is marked by extensive cell movement where the cells of the blastula/blastoderm become organized into THREE layers:
1. Ectoderm (outer)
2. Mesoderm (middle)
3. Endoderm (inside)
What is the ectoderm made of?
it is the outer layer that happens during gastrulation: structures formed on the outside of the embryo, skin and nervous system
What is the mesoderm made of?
These are structures made in the middle, they compose of bone, blood, muscle and some organs like the kidney.
What is the endoderm?
This is the final layer (inside): two tubes and associated organs - respiratory tract and the digestive tract
What is Neurulation?
the formation of the neural tube - special type of organogenesis (form the entire nervous system woahhh)
What is the first operational organ system?
The circulatory system is the first, heart is the first organ.
What are the three things involved in building an animal embryo?
- cell division
- cell differentiation
- Morphogenesis
How are genes turned on and off?
genes in specific cells are controlled by specific transcription factors that bind to gene specific “enhancers”
How does cellular differentiation happen?
It happens progressively as the embryo develops, earliest changes do not involve visual changes, might only show at a molecular level
What allows differentiated cells to carry out their specialized role?
They produce specialized proteins that help them to do this
What is morphogenesis?
The emergence of shape and structure in the body plan of the developing embryo
What is induction?
Adjacent cells/tissues communicating with each other, achieved at a molecular level through local cell signaling
Why are drosophila so important? (fruit flies)
They are important because they allowed us to understand genes that affected the body plan
What are the three classes of genes and what do they do?
- maternal genes: establish poles and axes
- Segmentation: divide the body into segmental units
- Homeotic genes: when mutated parts of the body end up in the wrong place
What are homeotic genes?
mutations change the identity of body parts, structures characteristic of a particular part of the animal arise in the wrong place
What do Drosophila body plan genes encode?
- Components of cell signaling pathways that allow cells to communicate (basis of induction)
- Transcription factors
What are Hox genes?
special set of genes that encode transcription factors, they are the genes mutated in homeotic mutants. Control the identity of body parts.
Why are limbs a good way to model morphogenesis?
They are a good model for how positional info is organized leading into morphogenesis.
- found relatively late in development
- external position
- obvious 3D pattern
What is a role of cartilage?
Cartilage condenses within the mesenchyme to mark out the future skeleton of a limb.
What are organiser cells?
A group of cells that influence the development of surrounding tissue.
What are the 2 important organisers found in the limb?
- The Apical Ectodermal Ridge (AER)
- The Zone of Polarizing Activity (ZPA)
What happens if the AER is removed?
If the AER is removed the limb stops growing
How is induction by cells achieved?
By cell signaling to neighboring cells - paracrine signaling (genes can be turned on and off in response to signals received.
How is cell signaling specific?
Only cells that posses specific receptors on their surfaces can respond in a particular way
meaning: some cells will not respond at all to a signal
- two different cells can respond in different ways to the same signal
What is the hedgehog gene?
First identified in the drosophila
- important developmental signaling pathway
-vertebrates have 3 homologues of drosophila hedgehog
Ihh, Dhh, Shh
What is the hedgehog role in drosophila?
it is a segmentation gene, establishes the para-segment boundary
What is the role of the hedgehog gene in mice?
- Bone formation (Ihh)
- patterning the neural tube (Shh)
- Male reproductive system (Dhh)
What are responsible for human limb malformations like polydactyly?
The sonic the hedgehog gene is (Shh)
What is Wnt signaling?
- Wnt signaling proteins are critical in patterning somite’s, development of nervous and muscle systems in the limb
How is gene expression detected in an embryo?
It is detected by the presence of mRNA specific for that gene within the cell.
- you can use reporter genes as a method
How is the state of a cell determined?
When it can no longer respond to changing environmental signals and change its differentiation pathway.
What is Specification?
Early commitment to the fate of the cell but can still be changed
What is determination?
the information received by a cell has fixed its fate and will allow no further change.
What are real examples of morphogens?
The maternal effect gene, bicoid on drosophila, role in axes establishment
- Elegans vulval development
What is the Hippo pathway?
it is known to act as the sensor of a cells environment
- Hippo mutation leads to tissue overgrowth
What are stem cells?
they are defined as undifferentiated cells that are both self renewing and can give rise to differentiated cells when stimulated to do so.
What are the different types of Stem cells?
Adult stem cells: some tissues require constant renewal, skin, intestine, muscle, blood (in your bone marrow)
Embryonic stem cells: ESCs are derived from the inner mass of the mammalian blastocyst, no specification, grown and cultured
What can stem cells do?
They can be cultured into organoids, structures that mimic aspects of tissues and organs
What is Pax6?
Pax6 is the master regulator of eye development
- highly conserved through evolution
- In Drosophila there is a loss of eyes
- In mice its called small eye syndrome
- humans malformation of the iris
