Juxtacrine signal transduction

signaling between cells that are touching

What signaling molecules use intracellular receptors? (4)

steroid hormones

thyroid hormone

vitamin D₃

retinoic acid

ligand (cell signaling)

molecule that binds to a receptor protein

agonist

ligand that activates signal transduction

antagonist

ligand that inhibits signal transduction

ligand specificity

ligands have different effects in different cells

ex: acetylcholine

kinases target: (3 aa)

serine

threonine

tyrosine

Ca²⁺ role in intracellular signaling

second messenger

cyclic AMP (cAMP) role in intracellular signaling

second messenger

GMP role in intracellular signaling

second messenger

DAG (diacylglycerol) role in intracellular signaling

second messenger

IP₃ role in intracellular signaling

second messenger

tyrosine kinase role in intracellular signaling

enzyme effector

adenylyl cyclase role in intracellular signaling

enzyme effector

it's an integral membrane protein

in general, phosphatases (activate/inactivate) and kinases (activate/inactivate) enzymes

phosphatases inactivate

kinases activate

Accessory proteins

necessary for intracellular signaling--facilitate interactions by binding and concentrating soluble signaling molecules to spec subcellular locations

3 typers:

Scaffold proteins

adaptor proteins

anchoring proteins

G proteins

bind and hydrolyze GTP (GTPases)

3 mechanisms of termination of signal transduction

1. reduce agonist availability

2. internalize and/or degrade agonist-receptor complex

3. modify receptor to inactivate it

Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin

receptor tyrosine kinases

3 domains: amino terminal (extracellular), transmembranous, carboxyl terminal (intracellular)

tyrosine kinase activation

binding of growth factor to receptor triggers dimerization, activating the kinase domain-->self-phosphorylation-->activation-->anchoring sites for other proteins-->signal cascade

Ras

GTPase (GDP bound--inactive, GTP bound--active) involved in cell proliferation

elevated expression in ~30% of tumor cells

MAP (mitogen-activated protein) kinases

Ras (GTPase)

activates

MAP kinase-kinase-kinase

which activates

MAP kinase-kinase

which activates

MAP kinase
which alters gene expression and/or cytosolic/membrane protein activiity

Transporting Growth Factor-β (TGF-β) and Bone Morphogenic Proteins (BMP)

growth regulatory factors required for fetal/neonatal development and maintenance of differentiated phenotype in adults

mutations-->CANCER

binding to receptors-->dimerization/activation of serine-threonine kinases

serine-threonine kinases

dimerize and activate upon binding of TGF-beta and BMP

recruit and phosphorylate SMADs, which bind DNA regulatory proteins in nucleus, activating or depressing gene expression

SMADs

bind to DNA regulatory sequences, activating or depressing gene expression

activated by serine-threonine kinases

part of BMP/ TGF-β signaling cascade

Cytokines

autocrine/paracrine regulators of growth and differentiation

include interleukins and interferons

cytokine binding to membrane receptors

dimerization, binding to cytoplasmic nonreceptor tyrosine kinases

-->activate STATs thru phosphorylation/dimerization-->bind to genes and activate DNA

-->also activate NFκB (involved in immune/inflammatory response) or MAP kinases

GPCR (G Protein Coupled Receptors)

structure

superfamily of receptors--7 α-helical transmembrane-spanning domains

beta and gamma subunits are similar in all types, alpha subunit varies (specificity)

alpha subunits contain sites of interaction/binding

GPCR α_I vs α_S

I=inhibitory (adenylate cyclase-->dec cellular cAMP)

S=stimulatory (adenylate cyclase--> inc cellular cAMP)

GPCR

basal state

active state

deactivation

basal state: bound to GDP, heterotrimeric structure

active state: bound to GTP, α subunit detaches

deactivation (signal termination): phosphorylation of receptor by kinases (e.g. PKA)

cAMP synthesis and degradation

synth: ATP + adenylyl cyclase--> cAMP

degradation: cAMP +cAMP phosphodiesterase (PDE)-->AMP

adenylyl cyclase

transmembrane protein, when activated/inactivated by G proteins, inc/dec cAMP production

PKA and cAMP

PKA inactive=tetramer w cAMP binding sites

cAMP binding-->dissociation, exposes kinase sites

PKA phosphorylates CREBs, which control expression of cAMP-responsive regulatory elements (CRE)

CREBs

control expression of CRE, important in gene activation

regulated by PKA, which is activated by cAMP

cGMP

action

synth/deg

regulates cellular contractility and blood volume homeostasis

activates PKG, binds heme, stimulated by NO

synth: guanylate cyclases

degradation: cGMP phosphodiesterases

Ca²⁺ based signal transduction

channels contain IP₃ receptor, a second messenger generated by phospholipase C (stim by hormones/NT)

cross talk

cells are subjected to many many stimuli @ any given moment