Lecture 2: Cell signaling Flashcards
What are the 3 steps of cell signaling and what do they do?
Reception: target cell senses the substance in its exogenous environment. (intercellular signaling)
Transduction: Conversion of the signal via a cascade of molecular events (intracellular signaling)
Response: specific cellular effect attributed to the signaling molecule
What are the reception modes of intercellular signaling?
Juxtacrine, Endocrine, Synaptic, Paracrine and Autocrine
What is contact-dependent intercellular signaling?
Requires cells to make physical contact with one another (receptor contact)
What is contact-independent intercellular signaling?
Cells do not make physical contact
Which reception mode of intercellular signaling is contact-dependent?
Juxtacrine (Lecture 2 slide 45)
Which reception mode of intercellular signaling is contact-independent?
Endocrine, Synaptic, Paracrine, Autocrine
Which mode of intercellular signaling target receptors reached through bloodstream?
Endocrine
What does the endocrine mode of intercellular signaling do?
Target receptors reached through the bloodstream
Which mode of intercellular signaling target receptors on nearby cells?
Paracrine
What does the paracrine mode of intercellular signaling do?
Target receptors on nearby cells
Which mode of intercellular signaling targets receptors using an electrical signal?
Synaptic
What does the synaptic mode of intercellular signaling do?
Targets receptors using an electrical signal
Which mode of intercellular signaling targets receptors on the same cell?
Autocrine
What does the autocrine mode of intercellular signaling do?
Targets receptors on the same cell
Is transduction cell signaling intracellular or intercellular?
Intracellular
Is reception cell signaling intracellular or intercellular?
Intercellular
What are the 2 properties tissues capable of responding to hormones have in common?
1) Posses a receptor having a very high affinity for hormone
2) the receptor is coupled to a process that regulates the metabolism of the target cells.
What are the secreted molecules (ligand) during transduction?
Hormones: peptide hormones, sterioid hormones
Neurotransmitters
Peptides
Lipids
List the intracellular receptors (receptors for secreted molecules)
Steroid hormones, estrogen, androgen
List the cell surface receptors (receptors for secreted molecules)
Peptide hormones, growth factors
What are the steroid hormone receptors?
Glucocorticoid receptor, estrogen receptor
Where is the glucocorticoid receptor located and what does it do?
Cytosol
Upon binding to a glucocorticoid, it translocates into the nucleus and activates transcription of a gene
Where is the estrogen receptor located and what does it do?
Nucleus
Upon binding to the hormone, it activates transcription
What are the 2 types of steroid hormone receptor activities?
Genomic action = slow (minutes): lasts longer
Non-genomic action = rapid (seconds): simple turn on and off
What is estrogen synthesized from?
Cholesterol
What are the major subtypes of estrogen receptors?
ERα and ER (beta)
What do ERα and ER beta do?
Exert differential effects on growth and differentiation in tissues
Where are estrogen receptors found?
All over the body (CNS, breast, liver, bone, cardiovascular system, GI tract, urogenital tract)
TA Lecture 1 Part B, slide 10
What is SERM?
ER ligands which exhibit antagonistic or agonistic activity depending on the tissue
What do SERM (Selective Estrogen Receptor Modulators) do?
Induce structural changes, affect the ability to interact with cofactors, different effects gene expression
What drug is the 1st SERM used in clinic and what is it used for?
Tamoxifen (non-steroidal), used in ERα positive breast cancer
Is Tamoxifen an antagonist or agonist receptor in the breast?
Antagonist
TA Lecture 2 Part A, slide 11
Is Tamoxifen an antagonist or agonist receptor in the uterine?
Agonist
TA Lecture 2 Part A, slide 11
What are examples of cell surface receptors?
Growth factors, EGF (epidermal growth factor), insulin
All receptors are what type of receptors?
Transmembrane
What type of hormones bind to cell surface receptors?
Hydrophilic
What activates secondary messengers within the cell?
The binding of the hormone to its receptors
The activation of secondary messengers within the cell leads to ______ ______.
signal transduction
What are the 3 domains of cell surface receptors?
Extracellular, Transmembrane, Intracellular
What are the major classes of transmembrane receptors?
1) Ligand-gated ion channels
2) Enzyme-linked receptor
3) Cytokine receptors
4) GPCR (G-protein coupled receptors)
What happens in ligand-gated ion channels?
ligand binds to receptor, causing a change in membrane potential
TA Lecture 2 Part A, slide 15
Explain enzyme-linked receptor (Tyrosine Kinase) pathway
1) Receptors activate tyrosine kinase or serine/threonine kinase activity in the cytoplasmic domain of the receptor
2) This leads to phosphorylation of intracellular signaling molecules and signal transduction
Has intrinsic kinase activity
Lectures 1&2, slide 63-65
TA Lecture 2 Part A, slide 17
Explain Tyrosine Kinase with RAS GTPase
1) Growth factor binds to ligand binding site
2) Upon binding, tyrosine kinase receptors dimerize
3) Dimerization activates tyrosine kinase phosphorylation
4) Adaptor protein binds to phosphate and recruits ras-activating protein
5) Ras bound to GDP = inactive, Ras bound to GTP = active
6) Active Ras goes on to downstream signaling pathways (MAP kinases)
TA Lecture 2A, slide 19
What do cytokine receptors not have? What pathway are they associated with?
Do not have intrinsic kinase activity, associated with protein kinase family (JAK-STAT)
Explain the JAK-STAT pathway
1) Cytokine (IL-6, NF𝜅B, IFN𝜶) binds to the cytokine receptor
2) Activated cytokine receptors recruit JAK to the cytoplasmic domain
3) JAK phosphorylates tyrosine kinase receptors
4) STAT bind to phosphorylated tyrosine kinase receptors
5) Activated/phosphorylated STATs dimerize and translocate to the nucleus = activate transcription genes
TA Lecture 2B, slide 2
Provide examples of cytokines
IL-6, NF𝜅B, IFN𝜶
Which receptors is the most common receptors?
G-Protein Coupled Receptors
How many transmembrane domain receptors does GPCR have?
7
What are the 4 subclass types of G-proteins? What do they do?
𝜶i - inhibits adenyl cyclase = decreases cAMP, phospholipases, phosphodiesterases
𝜶s - stimulates adenyl cyclase = increase cAMP
𝜶q - activates phospholipase C
𝜶l2 - Rho GEFs
In the GPCR signaling cascade, what does cAMP activate?
Protein kinase A
In the GPCR signaling cascade, which enzyme breaks down cAMP?
Phosphodiesterase
In the GPCR signaling cascade, phospholipase activates the conversion of _____ to ____ and ____.
PIP2 to DAG and IP3
In the GPCR signaling cascade, DAG activates what?
PKC (protein kinase C)
In the GPCR signaling cascade, what does IP3 cause?
The release of Ca+2 from ER
Provide examples of secondary messengers
Ca2+ ion, 3’,5’-cyclic AMP, 3’, 5’ cyclic GMP, DAG, IP3
What are the two ways PKC can be amplified?
G-protein linked receptor or Receptor tyrosine kinase
Explain the modes of downregulation
a) Receptor inactivation - active receptor leads to signaling cascade, desensitized receptor leads to uncoupling from signaling cascade
b) Receptor internalization - receptor internalized and recycled
c) Receptor down-regulated - receptor internalized and degraded
What drug is used to treat HER2-positive breast cancer?
Herceptin (Trastuzumab)
How does Herceptin work?
Herceptin attaches to HER2 receptors and blocks it which inhibits the cells to grow and divide
How do antibody conjugates work?
Use antibody to find target antigen and bind to lymphoma cell, thus allowing toxin to kill lymphoma cell
