Molecular Fundamentals - Signal Transduction II

what is kinase?

enzyme that adds a phosphate to another protein (substrate)

what is phosphatase?

enzyme that removes a phosphate from another protein

what are the three major amino acid targets for phosphorylation?

• serine

• threonine

• tyrosine

do enzyme-coupled receptors have a slow or fast response?

slow (hours)

what is the largest class of enzyme coupled receptors?

receptor tyrosine kinases (RTKs)

most extracellular signals for growth, survival, and proliferation act through what?

RTKs (receptor tyrosine kinases)

enzyme-coupled receptors initiate what?

a signaling cascade via phosphorylation events

activation of RTKS requires what?

dimerization

upon binding of signaling molecule, inactive RTK monomers come together to form what?

a dimer

in activation of RTKs, contact between the two adjacent intracellular receptor tails activates what and causes what?

the kinase function, and each receptor unit phosphorylates the other on specific tyrosines

the phosphorylated tyrosines can serve as what?

docking sites for “adaptor proteins” that will relay the signal inside the cell

most RTKs activate what?

Ras

what is Ras?

a small GTP-binding protein

when GTP is bound to Ras, it is what?

on (active)

when GDP is bound to Ras, it is what?

off (inactive)

activated Ras initiates what?

a phosphorylation cascade

the mitogen activated protein (MAP) kinase pathway is what?

an important signal transduction pathway involved in cell growth and proliferation

mutations in RTKs can lead to what?

unregulated cell proliferation

what does EGFR (epidermal growth factor receptor) do?

stimulates cell growth, proliferation, and differentiation

insulin receptor is what?

an RTK

what does insulin receptor do?

• induces protein synthesis

• regulates glucose transport and glycogen synthesis

what acts to increase glucose uptake and glycogen synthesis?

phosphorylated (active) Akt

what produces phosphorylated (active) Akt?

an active insulin receptor

what works in a similar mechanism of action as receptor tyrosine kinases (RTKs) except they phosphorylate serines and threonines instead?

receptor serine/threonine kinases

after the phosphorylation of receptor serine/threonine kinases, SMAD binds to the intracellular tail of the receptor and what happens?

SMAD is phosphorylated by the activated receptor

phosphorylated SMAD forms a complex with regulatory proteins and does what?

translocates to the nucleus where it serves a regulator of gene expression

what are cytokine receptors?

receptors for signaling molecules that control growth and differentiation of leukocytes

cytokine receptors do not hae what?

intrinsic kinase activity, they associate with other proteins that do have tyrosine kinase activity

binding of cytokine causes what?

dimerization of receptor

once the cytokine receptor is dimerized, what happens?

associated tyrosine kinase (JAK) is activated

JAK phosphorylates the intracellular tail of the receptor at specific tyrosine sites to serve as what?

docking sites for STAT

STATS are phosphorylated, dimerize, translocate to the nucleus, and serve as what?

transcriptional regulators for the expression of specific genes

for cytokine receptors, what activates proteins?

phosphorylation

for cytokine receptors, what deactivates proteins?

dephosphorylation

what describes receptor desensitization?

if repeatedly exposed to a particular signaling molecule, a cell can adapt its sensitivity to that molecule

what are the methods a cell uses to desensitize itself to a particular signaling molecule?

• inactivation of receptor

• internalization of receptor

• down-regulation of receptor

what describes inactivation of receptor?

structural modification of the receptor, resulting in its inactivation

what describes internalization of receptor?

• receptor/ligand complexes are incorporated into endosomes

• results in fewer receptors on the plasma membrane at any given time

what describes down-regulation of receptor?

• receptor/ligand complexes are incorporated into endosomes

• endosomes fuse with lysosomes

• degradation of the receptor and ligand occurs in the lysosome

what describes juxtacrine cellular communication?

signal-producing cell communicates directly with a neighboring cell

what describes synaptic cellular communication?

neurons release neurotransmitters that act on postsynaptic target cells

what describes membrane diffusible molecules cellular communication?

small hydrophobic signaling molecules can directly pass through the plasma membrane

what are types of juxtacrine signaling where a protein on one cell surface interacts with a receptor on an adjacent cell?

• notch signaling

• Fas

what is utilized when ligands in the extracellular matrix secreted by one cell interact with their receptors on neighboring cells?

integrins

what is utilized when there is direct transmission of signals from the cytoplasm of one cell to the cytoplasm of an adjacent cell?

gap junctions

what is an important mode of signaling in organogenesis (neurogenesis)?

notch signaling

notch signaling is activated upon binding to what?

delta, serrate, or jagged

in notch signaling, the cleaved domain translocates where?

to the nucleus and induces transcription of target genes

what is lateral inhibition?

a type of cell-cell interaction whereby a cell that adopts a particular fate inhibits its immediate neighbors from also adopting that fate

lateral inhibition is mediated by what?

notch-delta interactions (notch signaling pathway)

what describes Fas signaling?

upon binding to ligand to receptor, the cell expressing the receptor will under apoptosis

what is the death receptor that initiates apoptosis?

Fas signaling

integrins are what?

transmembrane heterodimers

when a ligand is secreted by a cell and deposited into the extra-cellular matrix, what happens?

integrin dimers on a nearby cell bind to the ligand in the ECM

an intracellular signaling cascade that is initiated by integrin dimers binding to the ligand in the ECM can influence what?

• cell proliferation

• cell survival

• cell migration

what are channels spanning the plasma membranes of two adjacent cells?

gap junctions

gap junctions allow what?

small water-soluble molecules and ions to pass between the two cells

gap junctions can be what in response to extracellular signals?

open or closed

what are found in the intercalated disc that connects adjacent cardiac muscle cells?

gap junctions

what do gap junctions allow for in cardiac muscles?

the flow of ions between the connected cells, propagating action potentials throughout the heart, and causing synchronized muscle contractions

what is a type of paracrine signaling that is specific to nerve cells?

synaptic signaling

the synapse between a neuron and its target cell constitutes what?

a restricted extracellular space into which neurotransmitter are secreted

what is an example of a membrane diffusible molecules that is a dissolved gas that can slip across the membrane to the cell interior and directly regulate the activity of specific intracellular proteins?

nitric oxide (NO)

what is an example of membrane diffusible signaling molecules that are small and hydrophobic, can pass through the plasma membrane directly and enter the cytoplasm, where they bind to intracellular receptors?

steroid hormones

nitric oxide is what?

a relaxant (causes relaxation of blood vessels)

acetylcholine is released from the nerve terminal of an activated neuron which causes what?

increased calcium release into cytoplasm that activates nitric oxide synthase

nitric oxide synthase does what?

uses arginine to produce NO

in the cytoplasm of the smooth muscle cell, nitric oxide binds to what?

guanylyl cyclase and activates it

what happens after nitric oxide binds to guanylyl cyclase?

it produces cyclic GMP, which causes the smooth muscle to relax

steroid hormones bind to what?

intracellular receptors in the cytoplasm

thyroid hormones bind to what?

intracellular receptors in nucleus