Cell Signaling Flashcards
What are the different modes of cell-cell signaling? How is each type of signaling carried out by the cell?
Endocrine: hormones are secreted and carried through circulation system to act on target cells at distant body sites (ex: estrogen).
Paracrine: a molecule is released from one cell and acts locally to affect a nearby target cell (ex: NT).
Autocrine: a cell produces a signaling molecule to which it responds itself (ex: immune system, where T cells respond by synthesizing growth factor).
What characteristics of steroid hormones enable them to carry out their mode of signaling?
Hormones are lipophilic, and can diffuse across the plasma membrane to intracellular receptors.
What are the major steps in glucocorticoid signaling?
1) glucocorticoids diffuse across the plasma membrane.
2) they bind to the inactive glucocorticoid receptor attached to HSP90 in the cytoplasm - this binding removes HSP90, and forms the active receptor dimer
3) the receptor dimer translocates to the nucleus, binds to DNA< and associates with coactivators like HAT (histone acetyltransferase) to stimulate transcription of target genes)
How are genes under the control of the thyroid hormone receptor regulated? Specifically, what role do HDAC and HAT have in switching these genes on and off?
In the absence of thyroid hormone: the hormone receptor is empty and so it binds to HDAC, and transcription is repressed.
In the presence of thyroid hormone: the hormone binds to the thyroid receptor, there’s a conformational change, and HDAC is removed and replaced with coactivator HAT (active), and transcription is activated
What is the role of nitric oxide in stimulating synthesis of cyclic GMP? What is the mechanism of signaling used by these small gas molecules?
1) a release of neurotransmitters such as acetylcholine
2) neurotransmitters act on endothelial cells to stimulate NO synthesis
3) NO diffuses to neighboring smooth muscle cells, which activates guanylyl cyclase
4) guanylyl cyclase turns GTP into cGMP
5) cGMP induces muscle cell relaxation and blood vessel dilation
How does nitroglycerine work in the treatment of heart disease (with a focus on cell signaling by NO)?
Nitroglycerin converts to nitric oxide in the body and stimulates vasodilation, which increases blood flow to the heart
What are the main groups of peptide signaling molecules?
Peptide hormones: insulin and pituitary hormones (growth hormone, FSH, etc.)
Neuropeptides: enkephalins and endorphins (natural analgesics)
Growth factors: nerve growth factor (NGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).
What is the basic structural unit of a peptide signaling molecule?
Amino acid
Do peptide signaling molecules act at the surface of the cell, or do they cross the plasma membrane?
They are unable to cross the plasma membrane of their target cells, so they act by binding to cell surface receptors.
What are the structural characteristics of G protein-coupled receptors?
- N terminus on the extracellular matrix side of the membrane, which has a ligand-binding domain
- intracellular C terminus with a ligand-binding domain and a guanine nucleotide exchange factor (GEF)
- carbs for folding
- 7 transmembrane alpha helices
What does GEF do?
facilitates the exchange of GDP for GTP
G protein-coupled receptors typically have carbohydrate groups attached to the extracellular portion of the protein. What is the role of these carbs?
Aid in receptor folding
What are the three subunits of a G protein?
Alpha, beta, and gamma; when a hormone binds to the G-protein receptor, this stimulates the release of GDP from the G protein on the inside of the cell, and attachment of GTP instead. The alpha subunit detaches from the beta-and-gamma subunits, and then they all go to their target enzymes or ion channels. When the bound GTP is hydrolyzed back to GDP, the alpha subunit reattaches itself to the beta and gamma units, and they all go back to the G protein receptor.
What are the main steps leading up to the hormonal activation of adenylyl cyclase by the hormone epinephrine?
1) epinephrine binds to the extracellular matrix side of the G protein receptor
2) this binding causes a conformational change, which activates the alpha subunit G protein
3) the G protein (and ATP) then goes over to adenylyl cyclase and causes it to make cAMP
What role do GTPase activating proteins (GAP) have in regulating G-protein signaling?
GAP induces GTP hydrolysis and inactivates a G protein
What are the main steps leading to the regulation of glycogen breakdown?
1) epinephrine binds to the extracellular matrix side of the G protein receptor
2) this binding causes a conformational change, which activates the alpha subunit G protein
3) the G protein (and ATP) then goes over to adenylyl cyclase and causes it to make cAMP
4) cAMP activates protein kinase A, which consists of two regulatory (R) and two catalytic (C) subunits in its inactive form. Binding of cAMP to the R subunits induces a conformational change
5) this conformational change causes the C subunits to dissociate and become enzymatically active
6) the C subunits activate phosphorylase kinase
6) phosphorylase kinase activates glycogen phosphorylase
7) glycogen phosphorylase causes the breakdown of glycogen to glucose-1-phosphate
Which amino acid residue is phosphorylated in glycogen breakdown?
a serine residue
How does cholera toxin negatively impact the normal signaling pathway for adenylyl cyclase activation - specifically, what is the mechanism of action for cholera toxin?
Cholera toxin inhibits the ability of the alpha subunit of G proteins to hydrolyze (turn off), meaning that the G protein is always active. This leads to overproduction of cAMP, which disrupt normal cellular processes.
How is protein kinase A regulated (activated/inactivated)?
It’s activated by cAMP, and inactivated when cAMP is converted to AMP
What are the main steps that lead to expression of cAMP-inducible genes?
1) cAMP binds to the R subunits of protein kinase A, causing a conformational change
2) the conformational change causes the C subunits to dissociate and activate
3) each C subunit translocates to the nucleus, where it phosphorylates the transcription factor CREB (CRE-binding protein)
4) this causes the recruitment of coactivators and the expression of cAMP-inducible genes
Contrast receptor tyrosine kinases and nonreceptor tyrosine kinases.
Signals: RTK use growth factors (paracrine) and NRTK use cytokines (autocrine).
Location: RTK are transmembrane and NRTK are cytosolic.
Function: RTK are growth and differentiation, and NRTK are immune and cytoskeleton.
NRTK do not have signal transduction.
What are the main steps that lead to activation of receptor tyrosine kinases?
Growth factors attach to the extracellular ligand-binding domain. The receptor dimerizes, and the dimerized polypeptide chains cross-phosphorylate each other (autophosphorylation). The activated receptor binds to the SH2 domains on downstream signaling molecules
What is the role of Ras in ERK MAP kinase signaling (specifically, how is Ras regulated)?
Ras is the crucial molecule that begins the signal transduction of the cascade. Ras is activated when GTP and GEF bind to it, and inactivated by GAP hydrolysis (GAPs accelerate the hydrolysis of GTP to GDP)
Under what circumstances would Ras be directly responsible for causing abnormal cell growth?
If GAP hydrolysis did not occur, Ras would never be turned off, and it would constantly activate downstream signaling pathways and promote growth signals (this is cancer)
