What is a first messenger?
A first messenger is a signaling molecule that reach the cell from the extracellular fluid and bind to their specific receptors
- (Ex. Hormone, growth factor, mitogen, cytokine, chemokine).
- Hydrophillic 1st messengers bind extracellular receptors and transduce their signal across the plasma membrane
What is a second messenger?
A second messenger is a small, non-protein molecule that passes along a signal initiated by the binding of a ligand ("first messenger") to its receptor
What are some examples of second messengers?
- Cylcic AMP (cAMP),
- Cyclic GMP (cGMP),
- Calcium ion
- [DAG, IP3] - phospholipids
What is the first step in the signaling pathway?
(1) signal binds to extracellular site on transmembrane receptor
What is the second step in the signaling pathway?
(2) receptor activates a membrane associated switch - 2nd messenger (Calcium ion, cAMP, cGMP, phospholipids)
What is the third step in the signaing pathway?
(3) inner membrane associated switches activate one or more of the cytoplasmic siganling pathways
What is the fourth step in the signaling pathway?
(4) final target is a nuclear gene expression pathway, metabolic pathway, cytoplasmic organelle, or cytoskeletal filament system?
What are the two common master switches in cell-signaling?
- GTP binding
What does phosphorylation do in cell signaling?
Phosphorylation activates downstream signaling events
- kinases phosphorylate proteins can activate or deactivate protein function
- phosphotates remove phosphates which can activate or deactivate protein function (serine, threonine, and tyrosine)
What are the two types of guanine nucleotide-mediated receptors?
- Small G-protein-couple receptors
- Large heterotrimeric g-protein coupled receptors
How are small G proteins regulated?
They are ...
- activated when GTP is bound
- inactive when GDP is bound
What is Ras?
Ras is a small G-protein, it is not stimulated directly by the receptor but through an an adapter protein
How does NF1 regulate RAS?
NF1 regulates RAS by returning RAS to the inactive (GDP bound state)
What is a oncogene?
genes that when expressed at high level stimulate growth and proliferation
- RAS is a key oncogene in a number of human cancers
How do large heterotrimeric G-proteins work?
Binding of ligand to the receptor stimulates the interaction of the receptor with the GDP-bound heterotrimeric G protein. GEF induces exchange of GTP for GDP. Binding of GTP to the alpha subunit causes the release of the beta-gamma complex. The free alpha subunit activates effector molecule, transducing the signal. Hydrolysis of GTP stimulates the release fo the alpha subunit from the effector permitting the alpha subunit to rejoin another beta-gamma complex.
What is the first messenger in Jak-Stat pathway?
selected cytokines (proteins that stimulate cell growth proliferation of the immune system including interleukins and interferons)
What is the second messenger in the Jak-Stat pathway?
What is the receptor example for the Jak-Stat pathway?
A cytokine receptor with Kinase activity (usually a dimer)
How does cytoplasmic transduction occur in the Jak-Stat Pathway?
Receptor recruits Janus Kinase (JAK), which autophosphorylates itself and the receptor; phosphorylated receptor becomes binding site for the transcription factor STAT (signal transducer and activator of transcription); JAK phosphorylates STAT, which then dissociates, dimerizes and enters the nucleus to activate transcription of selected genes
What is the response target in the Jak-Stat pathway?
What is the first messenger in the RAS/MAPK pathway?
Growth factors (e.g. EGF), the purpose of this pathway is to stimulate cell growth and proliferation
What is the receptor example for the RAS/MAPK pathway?
Tyrosine kinase dimer
What is the second messenger in the RAS/MAPK pathway?
How does cytoplasmic transduction occur in the RAS/MAPK Pathway?
Receptor dimerizes upon growth factor binding and the intracellular domain autophosphorylates itself; phosphorylated dimer is a substrate for the binding of protein kinases that activates the small G-protein RAS; activated RAS phosphorylates Raf, which phosphorylates MEK, which phosphorylates ERK (MAPK). ERK (MAPK) enters the nucleus and activates selected transcription factors to stimulate selected gene expression.
What is the response target for the RAS/MAPK pathway?
What is the first messenger in the cAMP-PKA pathway?
selected peptide hormones (ex. adrenaline) - the purpose of this pathway is to stimulate transcription of specfic genes including regulators of metabolic pathways
What is the receptor example for the cAMP-PKA pathway?
Beta-adrenergic recptor (usually a 7-transmembrane receptor)
What is the second messenger in the cAMP-PKA pathway?
How does cytoplasmic transduction occur in the cAMP-PKA pathway?
Receptor activates alpha subunit of a large G-protein, which in turn activates membrane bound adenylate cyclase. Adenylate cyclase catalyzes formation of cAMP; cAMP binds to regulatory subunits of protein kinase A (PKA) causing their release, thereby activating the catalytic subunits of PKA. PKA enters the nucleus, phosphorylates cAMP response element binding protein; CREB binds to CBP and activates transcription of selected genes
What is the response target for the cAMP-PKA pathway?
What is the first messenger in the PI3K-AKT (PKB) pathway?
selected hormones and apoptosis control proteins - this pathway controls cell growth and apoptosis pathways
What is the receptor example in the PI3K-AKT(PKB) pathway?
receptor with extracellular and intracellular domains and intrinsic kinase activity
What is the second messenger in the PI3K-AKT (PKB) pathway?
How does cytoplasmic transduction occur in the PI3K-AKT (PKB) pathway?
Receptor dimerizes and autophosphorylates itself; phosphorylated receptor becomes binding site for various proteins including phosphoinositide kinase, which converts phosphatidylinositol diphosphate (PIP2) into phosphatidylinositol 4,5 bisphosphate (PIP3); PIP3 activates a membrane-bound kinase that activates the AKT(PKB) kinase; AKT can act on a variety of proteins that regulate metabolic pathways and apoptosis.
What is the response target for the PI3K-AKT (PKB) pathway?
apoptosis, transcription and translation apparatus
What is the first messenger in the IP3-PKC pathway?
selected growth factors, mitogens and immune signals (eg histamine) -
What is the receptor example for the IP3-PKC pathway?
Usually a 7-transmembrane receptor
What is the second messenger in the IP3-PKC pathway?
IPC, DAG, Ca2+
How does cytoplasmic transduction occur in the IP3-PKC Pathway?
Receptor activates large G-protein, which activates phospholipase C (PLC); PLC cleaves membrane bound PIP2 into free IP3 and membrane-bound DAG; IP3 binds to a calcium ion channel on the smooth endoplasmic reticulum, causing the release of Ca2+; DAG activates Ca2+-bound Protein Kinase C (PKC); activated PKC can phosphorylate a number of proteins involved in cellular regulation
What is the response target for the IP3-PKC pathway?
ER, Transcription aparatus