Introduction to Signal Transduction

What are the 4 types of Intercellular Cell Signaling

1. Endocrine signaling (Signal that travels throughout the circulatory system)

2. Paracrine signaling (cell release signals to another [close])

3. Autocrine Signaling (Cell release signaling that affects itself)

4. Contact-dependent signaling

What is Intracellular Signal Transduction

The Process by which a signal produces intracellular biochemical alterations that in turn modify the cell

What is the classic Signal transduction pathway that we have talked about

1. Stimulus binds to a receptor (internal or external)

2. This may cause a signal transduction enzymatic reaction

3. This either causes change in regulation of gene expression OR gene expression-independent change

4. Both will lead to some changes in cellular function

What is a domain?

What is a catalytic domain?

What is a interaction domain?

A Domain is a sequence of a.a that folds independently and retain their function when expressed in isolation

A catalytic domain tend to be some proteins that have some sort of enzymatic function

Interaction domains: Are selections of a protein that drive proteins into multi-protein complex (Think where the protein-protein interaction will occur).

Why are protein-protein interactions essential for cellular signaling (2)

• Recruit and confine signaling protein in appropriate subcellular location

• Determine the specificity with which enzymes interact with their target

What are some examples of following Protein interactions that we went over in class

• Phosphotyrosine binding domain (1)

• Phospholipid binding domains (1)

• Ubiquitin Processes binding domains (2)

• Cell Death - Related domains (4)

• Phosphotyrosine binding domain (1)

  • SH2

• Phospholipid binding domains (1)

  • PH

• Ubiquitin Processes binding domains (2)

  • Ring, Hect

• Cell Death - Related domains (4)

  • DD (Death domains), DED (death effector domain), BIR (baculovirus IAP repeat), BH ( (Bcl-2 homology domain)

Describe one Key Characteristic of the SH2 domain. How does this characteristic relate to the protein function

• SH2 domain has high affinity phospho tyrosine (pY)-containing peptides. But has low affinity for unphosphorylated protein

• This helps to ensure that when a protein is phosphorylated it can go to next steps of signaling path (but when its not phosphorylated it goes back0

What is the key Characteristic of the PH domain. What is function of this protein and where is it localized

• PH domain proteins are Characterized as having a well-defined binding site for the phosphates in headgroup of phosphoinositide (Think PIP2)

  • As there are multiple versions of PI, There are multiple PH domains that react with a specific PI-X protein.

• Binding to the phosphoinositide allows it to responds to lipid messengers. Therefore these protein domains are localized to the cellular membrane

What are the DD (Death domain) used for. And what role do they play in that function

What proteins is it present in

• DD are motifs that are involved in apoptosis

• Various proteins that are involved with apoptosis link together via the DD (Think what brings these protein together). The DD are able to dimerize to other DD which helps recruit proteins to a complex

• TNDR superfamily and cytoplasmic proteins

What are involved in DED (Death-Effector Domain) and function

What proteins is it involved with

DED is also involved with cell death

• inactive procaspases and proteins that regulate caspase activation

• These DED come together via homotypic interaction (two of the same domain interaction with each other) between two DEDs

What is BIR involved in

What is unique about BIR

How does BIR function

• BIR involved in apoptosis

• That all proteins in the IAP family contain at least one BIR domain

• BIR is important to interact with a wide range of proapoptotic factor

What is BH involved with

How many different BH domains are there other function

What are they all unique too

• BH is involved with mitochondrial apoptosis

• There are 4 different BH, have both anti-apoptotic and proapoptotic

• DH domains can all be found to the BCL=2 family

What is the main function of receptors

Ligand recognition is a required but not _______ characteristic of a receptor

What happens when translation occur

• The main function of the receptor is to bind and recognize a ligand and translate the information into a cell signal

• Ligand recognition is a required but not Sufficient characteristic of a receptor

• When translation occurs it implies amplification of the input information

What are the different aspects of the tyrosine kinases receptor (photo and 1 flashcrad)

What are the key role (4)

What is unique about the tyrosine kinase receptor

• The tyrosine kinases receptor is a single-pass transmembrane receptor

• Cellular growth, differentiation, metabolism and motility

• Receptor tyrosine kinase are have intrinsic tyrosine kinase activity

What is a key important concept of the tyrosine kinase receptor that we talked about (related to how many there are)

The extracellular (ligand binding area) domain of the receptor has a large variety of variation; however, the intracellular domain of the receptor (tyrosine kinase area) stays the same.

This allows the tyrosine kinase to recognize a variety of different signaling but have a similar signaling Reponse

How does the tyrosine kinase receptor activated

• Once the ligand is bound to the receptor the receptor goes under a conformation change that opens up the kinase domain and allows the active site to become available

True or false

The tyrosine kinase receptor active only triggers 1 signaling pathway

False

Tyrosine kinase receptor can trigger a multitude of different signaling pathways that end up in a change in transcription factors

What are two important domains that all enzymes

• Catalytic domain

• Interaction domain

What do kinases and phosphates enzymes do

• Kinases add an inorganic phosphate from ATP to a target protein

• Phosphatases normally remove a inorganic phosphate from a protein

What is ubiquitination, Ubiquitin ligase, DUBs

What are the two function that ubiquitination can regulate

• ubiquitination is the addition of ubiquitin to a protein

• Ubiquitin ligase is an enzyme that helps transfer a ubiquitin on proteins

• DUBs — help remove ubiquitin from proteins

• Ubiquitination is important as it regulates NFkB signaling (need to occur), Also important for the internalization of receptors (endocytosis) if the receptor is Ubiqulated

What is the function of GTPase

What activates and deactivates GTPase

• the main function of GTPases is that they are molecular switches ( Can either be turn off or on to terminate or start a signaling pathway)
  

• GEFs

  • GEFs convert GDP → GTP which activates GTPase

• GAPs

  • GAPs convert GTP → GDP inactivating GTPase (Gaps off a phosphate)

What do regulatory proteins contain and what do they not contain

What is the importance of regulator proteins

• Regulatory proteins contain interaction domains but not catalytic domain

• This allows separation of catalysis and input control into separate genes (redundancy)

What are the 4 possible functions of regulator proteins

1. Recruit and confine signaling proteins to an appropriate subcellular location

2. Couple cell surface receptors to intracellular biochemical pathways (bring receptors to interact with protein)

3. Drive signaling molecules into specific multi-protein complexes

4. Determine specificity of enzymes with their target

What are the 3 different types of regulator proteins that were mention in class

• Docking proteins

• Adaptors proteins

• Scaffolds proteins

What is the function of Docking Proteins

What are the 2 main aspect of docking proteins that was mention inn class

• Docking proteins function as platforms that help recruit signal protein to respond to a stimulate. (Stimulate occurs (conformation change in the receptor that interacts with the docking protein → interacting with the receptor causes the docking protein to have a conformation change that helps it recruit signaling protein)

• Docking protein contain a portion of protein

  • That interact with the membrane (usually made up of; PH domain, myristyl anchor, transmembrane domain)

  • Intracellular domain that is normally contain SH2 or other domains that help interact with signaling protein

What is the function of adaptor and scaffolding regulatory protein

What is the main different between adaptor and scaffolding protein

• Adaptor and scaffolds recruit specific enzyme or their up stream partner to the same complex (Think is a protein that holds two thing together so their in close proximity for a rxn to occur)

• The main difference between adaptor and

  • Adaptor protein is that adaptor hold 2 things together

  • Scaffolding holds 3 or more things together

True or False

“Adaptors and scaffolds allow catalytic proteins to play several distinct roles depending on the complex they form”

True

Different complexes can bring different protein to the same enzyme which can cause different downstream affects

What are the two main things that scaffolding proteins can recruit

What can the expression of these protein determine

How can these regulatory function be modified (think what happens when they are post-translated mortified)

• The scaffold/adaptor proteins can be either recruit positive or negative regulator protein (either stop are start signaling)

• The expression of these protein can determine the function the cell type has (Determine how much of a signal may occur)

• The scaffold/adaptor protein can undergo post-translational modification that can either inactivate or active the protein

What is the main point of cell signaling Cross talk

• The main point of having multiple pathways that cross talk with each other is to allow intricate control and integration

• And enables cells to coordinate multiple signals to ensure the appropriate cellular outcome occurs

What are the two main mechanism of feedback pathways that we talk about in class

• Positive feedback

  • amplify an initial signal

  • can change the response timing by accelerating or prolonging the time for the signal system to generate a response

• Negative Feedback

  • Inhibit or reduce signaling activity once a certain threshold is reached

Why is it important that we are able to terminal signaling pathways (2)

• It is important to maintain homeostasis (return back to a basal state and to prevent over stimulation)

• If no termination occurs may lead to the development of a diseases (if can’t stop immune system then have autoimmune disorder)

What are the 4 ways of signal termination that we talked about in class

• Termination of plasma membrane receptor signaling

  • Think phosphorylation/dephosphorylation or internalization of receptors

• Synthesis of protein termination signals

  • NFkB

• Degradation of signaling molecules

  • Enzymatic breakdown of second messengers (like cAMP)

• Activation of opposing processes

  • (Enzymes like GTPase and Phosphates — GAPs turn; GTP→ GDP)