Review of Cell Signaling

signal transduction

any process by which a cell converts one kind of signal or stimulus into another

• involves of a sequence of reaction carried out by enzymes and linked through second messengers

• millisecond to few seconds

signaling cascade

chain of steps in which an increasing number of enzymes and other molecules become engaged in the events that proceed from the initial stimulus

first messenger: chemical messenger, bind to receptors at cells

second messengers

molecules that relay signals recieved at receptors on the cell surface (NEVER PROTEINS)

• ex: signals such as the arrival of protein hormones, growth factors, etc. to target molecules in the cytosol/nucleus

• ex: cyclic nucleotides (cyclic AMP & cyclic GMP) and calcium ions (Ca2+)

amplify the strength of the signal

Extracellular signal molecule category

intracellular receptors (hydrophobic)

cell-surface receptors (hydrophilic)

Intracellular receptors

smaller class of signals that are SMALL or HYDROPHOBIC enough to

slips easily through the plasma membrane

activates intracellular enzymes or binds to intracellular receptors to regulate gene expression

ex: nitric oxide and cortisol

Cell-surface receptors

largest class of signals that are TOO HYDROPHILIC

to cross the plasma membrane of the target cell (transmembrane)

rely on cell surface receptors to relay messages into the cell

ex: insulin

Endothelial cells

specialized, flattened epithelial cells that line every blood vessel

nitric oxide

dissolved gas that diffuses out of endothelial cells & enters neighboring smooth muscle cells

• binds to the enzyme Guanylyl cyclase, stimulating formation of cGMP

• causes relaxation of smooth muscles of the blood vessels

Nitric oxide-smooth muscle relaxation pathway

1) Acetylcholine causes increased Ca2+ levels in the endothelial cells → NO synthase activates → creating nitric oxide

2) NO diffuses rapidly from the endo cells to the nearby smooth muscle cells

3) NO activates the enzyme guanylyl cyclase → stimulates formation of cGMP → muscle relaxes

Viagra

promotes smooth muscle relaxation in the vasculature

enhances the effects of NO by inhibiting the enzyme Phosphodiesterase (PDE)

• (PDE) normally breaks down cGMP, prolonging the NO signal, thus prolonging penile erection

Hydrophobic steroid hormones

cross the plasma membrane of the target cell

hormones bind to, and activate receptors found in the cytoplasm or nucleus

upon activation, hormone receptors are capable of rgulating gene transcription

ex: coritsol, estradiol, testosterone

Hydrophilic signaling receptors

G-protein linked receptors

ion-channel linked receptors

enzyme linked receptors

G-protein linked receptors

largest family of cell-surface receptors

all G-proteins have a similar structure and operate in a similar way

ex:

• trimeric G-proteins are composed of alpha, beta, y, subunits and are tethered to the membrane inside the cell

• inactive G-proteins are bound by GDP at the alpha subunit

G-protein pathway

1) hydrophilic signal binds to the extracellular side of the receptor → changes the shape of the receptor on the cytoplasmic side → exposes a binding site for the G protein

2) binding to the G protein to the receptor triggers the exchange of GDP with GTP by the alpha subunit → activating the G protein

3) G protein activation triggers a detachment of the alpha and the beta and y subunits from the receptor and each other → roam the plasma membrane

G protein subunits

activated alpha Betay G-protein subunits can both interact directly with target proteins in the plasma membrane that can relay the signal to other destinations

• complex remains dissociated and active until the alpha subunit hydrolyses the bound GTP to GDP

• GTP hydrolysis causes the alpha subunit to reassociate with the Betay subunits and the signal is SHUT OFF

If a G protein were unable to release its bound nucleotide but could hydrolyze it, signal transduction would

NOT move beyond this point

If a G protein could release the bound nucleotide but was not able to hydrolyze it, signal transduction would:

be continuous beyond this point

Trimeric G-proteins

Gs: activates adenylyl cyclase (adenylate cyclase)

Gq: activates phospholipase C

G protein Gs

activates adenylyl cyclase, an enzymes that catalyzes cyclic AMP (cAMP) formation

• cAMP 2nd messenger activates the enzyme protein Kinase A, involved in a wide range of biological processes including long-term memory

• cAMP is quickly degraded by phosphodiesterase

  • necessary to maintain sensitivity of the cell to extracellular signal

  • lack of degradation results in a failure of response to further extracellular signals

Caffeine

• acts as a phosphodiesterase (PDE) inhibitor

• similar to Viagra

Intracellular cAMP

activates gene transcription

• in cytosol, cAMP activates PKA → moves into nucleus → phosphorylates specific gene regulatory proteins

  • PKA can also phosphorylate proteins in cytosol

• phosphorylated proteins stimulate transcription of target genes

GTP bound G_Q

activates Phospholipase C

• phospholipids can be hydrolyzed into components that act as second messengers

• phosphatidyl inositol-biphosphate (PIP2) is hydrolyzed into inositol triphosphate (IP₃) and diacyglycerol (DAG) → both second messengers

• IP₃ → cytoplasm: binds to an opens calcium channels in the ER

• DAG → membrane: together with calcium activates the enzyme protein kinase C

Response to Epidermal Growth Factor Receptor (EGFR) to EGF binding

1. EGF interacts with the external domain of EGFR, triggering dimerization

2. Dimerization stimulates enzymatic activity of the intracellular catalytic domain → resulting in trans-autophosphorylation

3. downstream cytoplasmic proteins become activated by binding to EGFR phospho-tyrosine residues

4. downstream proteins build a bridge between the receptor tyrosine kinase (RTK) and the Ras protein, which is subsequently activated

Ras

monomeric G-protein that belongs to the small GTPase family

• small protein bound by a lipid tail to the cytoplasmic surface of the plasma membrane

• active when bound with GTP

• inactive when bound with GDP

first identified in human cancer cells → in which a mutation in the Ras gene produced a hyperactive form of Ras

• 30% of human cancers involve mutations of the Ras gene

• mutant Ras proteins are unable to dissociate GTP → stuck in the ON active conformation → constantly stimulating cell to divide

MAP kinase phosphorylation Cascade

Ras activates a phosphorylation cascade → series of protein kinases phosphorylate and activate one another in sequence

• named after the Mitogen-Activated-Protein, final kinase in the cascade

• at the end of the signal cascade, MAP-kinase phosphorylates regulatory proteins on serine and threonine residues

major communication systems in body

nervous system: specialized for rapid communication accomplished through electrical impulses in neurons

endocrine system

endocrine system

composed of glands and hormone-secreting cells located in various organs (such as heart, kidneys, liver, and stomach)

signals sent are more delayed and last longer compared to the nervous signals

One Gland → Multiple hormones

ex: pancreas secretes insulin (lowers blood glucose), glucagon (increases blood glucose) and somatostatin (inhibits secretion of pancreatic hormones)

• reflects the presence of different types of endrocrine cells in the same gland

• chemical messengers secreted by an endocrine gland cell may also be secreted by other cell types

  • ex: norephinephrine is used both as neurotransmitter in the nervous system and is an endocrine hormone secreted by the adrenal medulla