Ch.15 CSF

paracrine

extracellular signals diffuse locally through extracellular fluid and stay close to the vicinity of the cell that secretes it

autocrine

local mediators/signaling molecules act on themselves (ex. immune cells, can trigger their own response)

endocrine

involves endocrine glands (produces hormones) ex. pancrease: endocrine cells produce insulin to increase glucose uptake

synaptic

type of neuronal signaling, how nerve cells deliver messages

contact dependent

cells signal to each other by direct physical content

signal transduction

successive tranmission of signals and conversion of one type of signal into another type

local mediators

signals on nearby cells

neuronal signaling

axon terminates at synapses (specialized junctions), electrical signals convert to chemical signals at nerve terminal to release molecule

nitric oxide gas released by endothelial cells in the blood vessels diffuses to induce relaxation of adjacent smooth muscle cells

paracrine signaling

cell surface receptors

larger, polar molecules

intracellular receptors

small, nonpolar molecule

animal cell

depends on multiple extracellular signals

the same signal molecule can

induce different responses in different target cells

during nervous system development in drosphila, the membrane-bound protein Delta acts as an inhibitory signal to prevent neighboring cells from developing into neuronal cells

Contact-dependent

If signaling molecules act on the same cells that release them, it is an example of

autocrine signaling

classes of cell surface receptors

ion-channel coupled receptors, g protein-coupled receptors, enzymed-coupled receptors

ion-channel coupled receptors

signaling molcules help to open transmitter gated ion channels

• bind an extracellular signal to change permeability

g-protein coupled receptors

receptors coupled to g-protein, activates protein when bound to signaling molecule

enzyme coupled receptors

tend to be monomeric, could be dimeric, bound to membrane

• activate by dimerizing receptor

• or acticates protein that is now enzyme associated with receptor

g protein

• trimeric protein, 3 parts- alpha, gamma, beta

• 7 pass transmembrane protein

Molecular Switches

receipt of signal causes signaling protein to switch from inactive to active

• many intracellular signaling proteins act as molecular switches

signaling by phosphorlaytion

• ATP donates phosphate to phosphorylate tyrosine, and this regulates function

Amino Acids that can be phosphorylated

Thyrosine, Serine, Threonine

GEF

Guanine Nucleotide Exchange Factor- GDP → GTP to activate GTPase

GAP

GTPase Activating Protein- GTP → GDP, hydrolysis to deactivate GTPase

Monomeric GTPases are in “ON-State (active)” upon binding to

GTP

multiple inhibitory signals produce

a positive signal (negative times negative = positive)

signaling scaffold protein

• signaling factors bound directly to the scaffolding

signaling complex on activated receptor

phosphate groups recognized, diffuse and bind

between signaling diffuse complex and scaffold protein, which is more rapid

scaffold (more organized, ready to go)

assembly of signaling on phosphoinositide docking sites

kinase phosphorylates intracellular phosphates, amplifies signaling responses due to diffusing and spread of response

interaction domains

how proteins recognize each other and bind to each other with the help of domains signaling to each other

Formation of large receptor clusters

• by multivalent interactions between proteins

variables affecting response to a signal differ in pathways

• how far signal has to travel

• how soon will protein respond to signal

• how sensitive is the response to the molecule, how much concentration is needed

• integration, affinity, coordination of responses, etc

signal integration

downstream signaling response based

• multistep activation

slow or rapid responses to signals

• if protein is directly responded, very rapid (post-translational modifications of proteins, ex. phosphorylation)

• new protein/synthesis takes a lot longer (gene expression changes)

Which of these occur more rapidly in response to a signal?

A. Changes in Protein Phosphorylation

B. Changes in mRNA synthesis

A. Changes in Protein Phosphorylation

Feedback regulation of intracellular signaling

when "B” is inhibitor, negative feedback

when “B” is promoter, positive feedback

positive feedback loop with signal added

“E” can activate itself further, more of a robust response + increases (signal gone, response still stays).

negative feedback loop with signal added

inhibitor can remove from E; when signal added there is a short delay, but there is a subdued response

with long delay, there is more time before inhibition, where full response is seen

cell sensitivity

responses to a signal adapt depending on the goal and methods, overtime signal becomes more subdued (desensitization)

activation of cAMP-dependent Protein Kinase (PKA)

catalytic subunits have substrates that phosphorylate and add to downstream response

protein phosphatase

remove phosphates from serines, threonines, and tyrosines

dephosphorylates proteins, but not Ga

many GCPRs through G proteins activate

membrane bound phospholipase C-B

phosphatidylinositol (PI)

lipid tails connected to a phosphate, linked to inositol, or a sugar molecule

nitric oxide gas can

mediate signaling between cells (ex. endothelial cells + smooth muscle cells), rapid diffusion across membranes

gcpr desensitization depends on

receptor phosphorylation, after signaling must be turned off

arrestin

job is to arrest GCPR signaling, inhibits GCPR from functioning further and stops signaling response

enzyme coupled receptors

receptors are enzymes themselves or associated with enzyme

• types: serine threonine kinases or receptor tyrosine kinases

receptor tyrosine kinases

simulates cell survival and growth, cause cells to grow and synthesize

subfamilies of RTKs

exist as a monomeric subunit or come together and function as a dimer through a signaling domain

activation of RTKs

dimerization: interaction domains are used to stimulate assembly of an intracellular signaling complex (autophosphorylation), generates binding sites for signaling proteins

EGF receptor kinase

Epidermal Growth Factor is binded, and the receptor dimerizes

intracellular signaling proteins with SH2 domains can bind to

activated receptor kinases

• phosphorylates itself on receptor tyrosines, each one is recognized by something else with a SH2 domain

where does specificity come from in recognition?

the position/situation, the confirmation, and the variability of the placement

3D structure of SH2 domain

binding site for amino acid side chain, binding site for phosphotyrosine

The two monomers in a receptor tyrosine kinase dimer phosphorylate each other and the process is called

Trans-auto-phosphorylation

How does monomeric GTPase Ras mediate signaling

by most RTKs activating Ras

RTK activation of Ras

Ras is a monomeric GTPase, binds GTP and molecularly switches between GDP inactivity to GTP bound activity

Ras activate what

MAP (Mitogen Activated Protein Kinase) Kinase Signaling Module

• Raf Mek Erk pathway, kinase phosphorylates one, then another, then so on

scaffold proteins

help with cross talk between parallel MAP kinase modules

Pi3-Kinase pathway

phosphoinositide-3-kinase, adds phosphate at third position

• pi 3,4,5-triphosphate=key signaling molecule

activated AKT promotes

cell survival, inactivates BAD by phosphorylation

mTORC 1

essential pathway that activates translation initiation, triggers protein synthesis

gator complexes in MTORC 1

cytosolic amino acids increase, bind to amino acid receptors, releases inhibition of Gator two, which then inhibits gator 1 (Rag GAP)

TSC 1/ TSC 2

mutated in tuberous sclerosis, autosomal dominant disorder involving tumor formation in multiple organs

RTK and GCPRs activate overlapping signaling pathways

RTK deals with both pathways, pathways talk to each other to regulate downstream processes

Alternate signaling routes in gene regulation

lateral inhibition mediated during direct contact cells, inhibition of transformation around target cell

proteolytic cleavage

notch cleaved in Golgi to create hetero dimeric receptor recognized by delta protein, which is cleaved by a gamma secretase further into membrane, releases notch down into nucleus to bind to transcription factors

activation of nuclear receptors

inactive receptor bound to inhibitory proteins

ligand binds to ligand binding domain in active receptor