Cell Signal Transduction

function of cell signaling

• sensing stimulus

• cell-cell communication

• information processing

• decision making

key elements of cell signaling

• signals

• receptors

• signal transducers

• effector proteins

• functional changes

endocrine

cell signal released and circulates to whole body

paracrine

cell signal released and acts locally

synaptic

cell signal released and acts locally; requires neurotransmitter

contact-dependent

• cell signal not released and very localized

• signaling molecule stays attached to surface of signaling cell

fast response

post-translational modification b/c changing a protein that already exists

slow response

protein and transcriptional changes

types of extracellular signals

• proteins

• peptides

• amino acids

• nucleotides

• steroids

• fatty acid derivatives

• dissolved gas

types of intracellular signals

• sex hormones

• thyroid hormones

• steroids

• nucleotides

• small hydrophobic molecules

• metabolites

• vitamins

• dissolved gas

types of membrane receptors

• ion channel linked

• enzyme linked

• G protein coupled

receptor tyrosine kinase

largest enzyme-coupled receptor family

receptor tyrosine kinase activation

1) ligand binds to RTK receptor

2) receptors dimerize

3) receptor kinase activated

3) signal transduction proteins dock at phosphorylated Tyr

constitutively on is problematic because

how cancer happens

signal of activated RTK is often transmitted via

Ras

• small GTP-binding protein

• has GTPase activity

• has attached lipid that anchors it to membrane

Ras activates

• cascade of serine/threonine kinases

• Ras activates 3K —> phosphorylates 2K —> phosphorylates on K —> cellular changes by phosphorylation

Ras with mutation in GTPase is found in

human cancer; cannot shut itself off

guanine nucleotide exchange factor (GEF)

• activates intracellular molecular switches

• helps the protein release GDP and bind GTP

GTPase-activating protein (GAP)

• inactivates intracellular molecular switches

• helps the GTPase break down GTP → GDP

activated TOR

inhibits protein degradation and stimulates protein synthesis to increase cell size

PI 3-kinase phosphorylates

inositol phospholipids in membranes

G protein is heterotrimeric

• alpha, beta, and gamma

• alpha and gamma attached lipid anchors in membrane

• alpha binds GDP or GTP

G-protein-coupled receptor (GPCR)

• when signal binds, activated receptor undergoes conformational change

• G-protein alpha subunit swaps GDP for GTP

• beta and gamma dimer disassociates

activated G protein subunits

• activate a target protein

• produce second messengers to relay signal

hydrolysis of GTP to GDP

returns G protein to inactive heterotrimeric G protein associated w/ GPCR

activated G protein activates adenylyl cyclase to

make cAMP from ATP

activated G protein activates Phopholipase C to

make DAG and IP3

some activated G proteins can inhibit

adenylyl cyclase

cAMP is degraded by phosphodiesterase to

stop cAMP signal so it can remain responsive to external cues

caffeine inhibits

cAMP phosphodiesterase

effects of cAMP activating Protein Kinase A

1) fast path of glycogen breakdown

2) slow path of transcription of target gene