Cell Bio Chapter 15

Extracellular messenger molecules

transmits messages between cells

autocrine signaling

the cell has receptors on its surface that respond to the messenger

paracrine signaling

messenger molecules travel short distances (neighboring cells) through extracellular space

endocrine signaling

hormones are the messenger molecules and travels through blood stream

Ligand

the extracellular signaling molecule that specifically binds to receptors

receptor

on the cell membrane or in the cytoplasm. different cells have different ones

major routes for signaling

1. second messenger
2. cascade protein recruiting signaling

Effector

an enzyme responsible to generate second messenger molecules

cascade protein recruiting signaling

receptor serves as protein recruiting station

Signal transduction pathway

the overall process in which information carried by extracellular messenger molecules is translated into changes that occur inside a cell

Signal transduction pathway characteristics

* consists of a series of proteins
* each protein contains multiple domains (catalytic, regulatory, protein-protein interaction, etc)
* each protein in a pathway alters the conformation of the next protein
* phosphorylation alters the protein conformation (kinases add phosphate groups and phosphatases remove them)
* target proteins ultimately receive a message to alter cell activity

Protein phosphorylation

changes protein behavior in different ways

site of phosphorylation

1. serine
2. threonine
3. tyrosine

Function of phosphorylation

* activate or inactivate an enzyme
* increase or decrease protein-protein interactions
* change subcellular location of the protein
* trigger protein degradation

pattern differs between cell types

Extracellular messengers

* Amino acids (acetylcholine, epinephrine, dopamine)
* Gases (NO and CO)
* Steroids (regulate sexual differentiation, pregnancy, carbohydrate metabolism)
* Eicosanoids: lipids derived from fatty acids
* peptides and proteins

almost all bind to specific receptors to send signals

Receptor Types

* G-protein coupled receptors (GPCRs)
* Receptor protein-tyrosine kinases (RTKs)
* Ligand gated channels
* steroid hormone channels
* specific receptors such as B-and T-cell receptors

G protein-coupled receptors and their second messengers

* GPCRs are the single largest superfamily of proteins encoded by animal genomes
* have 7 a-helical transmembrane domains
* Natural ligands: hormones, neurotransmitters, opium derivatives, chemoattractants (odorants, tastants, photons)
* protein interaction domain: interact with G proteins inside

Activation of signal transduction by GPCRs

Step 1: ligand binds to receptor, alters its conformation and its affinity to bind to the G protein

Step 2: the Ga subunit releases its GDP then its replaced with GTP

Step 3: the Ga subunit dissociates from the Gby complex and binds to an effector and activates it

Step 4: activated effector produces cAMP

Termination of signal transduction for GPCRs Mechanism 1

Desensitization

Step 1: G protein-coupled receptor kinase (GRK) activates a GPCR by phosphorylation

Step 2: Arrestin proteins compete with G proteins to bind GPCRs

Desensitization

blocks active receptors from turning on additional G proteins

Termination of signal transduction for GPCRs Mechanism 2

Endocytosis of GPCRs

Function of Second Messengers for GPCRs

* diffuse inside the cytoplasm
* amplify the response to a single extracellular ligand

Common Second Messengers

* cAMP
* Ca2+
* Nitric oxide
* cGMP
* Phosphoinosides
* Inositol triphosphates
* diacylglycerol

Regulation of Blood Glucose Levels by GPCRs and their 2nd Messengers

* glucagon and epinephrine stimulate glycogen breakdown and inhibit its synthesis
* insulin stimulates glycogen synthesis and inhibit its breakdown
* cAMP evokes a reaction cascade that leads to glucose mobilization

Protein-Tyrosine phosphorylation as a mechanisms for signal transduction

* protein-tyrosine kinases functions by phosphorylating tyrosine residues on target proteins

2 types:


1. Receptor protein-tyrosine kinases (RTKs)


1. cell surface receptors of the protein tyrosin kinase family
2. 1 transmembrane domain
3. 1 ligand binding domain
2. non-receptor (cytoplasmic) protein-tyrosine kinase

Activation of receptor protein-tyrosine kinase (RTKs)

Dimerization of receptor results from ligand binding

2 mechanisms for dimerization:


1. ligand-mediated dimerization
2. receptor-mediated dimerization

protein-tyrosine phosphorylation as a mechanisms for signal transduction

* auto-phosphorylation sites on RTK functions in:
* regulation of receptor’s activity
* providing binding sites for cytoplasmic signaling molecules
* phosphotyrosine-dependent protein-protein interaction
* bind effector proteins that have SH2 domains and PTB domains

RTKs can interact with different signaling proteins

a) adaptors proteins: functions as linkers

b) docking proteins: supply receptors with additional tyrosine phosphorylation sites

c) transcription factors

d) signaling enzymes: (protein kinases, protein phosphatase, lipid kinase, phospholipase, GTPase) that lead to changes in cell

Termination of signal transduction by RTKs

* usually terminated by internalization of RTKs
* alternate fates after internalization
* degraded in the lysosomes
* return to the plasma membrane
* engage in continued intracellular signaling

insulin

regulates blood glucose levels by increasing cell glucose uptake

characteristics of Signaling by the insulin receptor

the insulin receptor is a protein-tyrosine kinase

* each receptor is composed of a and B chain
* are present as stable dimers
* inactive without insulin binding

Signaling by the insulin receptor

autophosphorylated receptor associates with a small family of docking proteins only

* insulin receptor substrates (IRSs)
* possess PTB-domain
* IRSs bind proteins with SH2 domains to activate downstream signal molecules
* PI 3-kinase (PI3K)
* Active PI3K produces phosphorylated lipids that trigger the activation of downstream proteins (Akt, PDK1)
* Terminal effects of PI3K activation include increased protein synthesis, glucose uptake, and glycogen synthesis

Diabetes Mellitus

* Type 1 diabetes
* 5-10%
* inability to produce insulin
* Type 2 Diabetes
* 90-95%
* Insulin resistance of target cells
* caused by a high-calorie diet combined with a sedentary lifestyle

Signaling Pathways

* Converge: signals form unrelated receptors can activate a common effector
* Diverge: identical signals can activate a variety of effectors
* Crosstalk: signals can be passed back and forth between pathways

Convergence

GPCRs, receptor tyrosine kinases, and integrins bind to different ligands but they all can lead to a docking site for Gbr2.

Crosstalk

more and more crosstalk is found between signaling pathways

* cAMP can block signals transmitted through the MAP kinase cascade

Apoptosis

an ordered normal process leading to the cell death in animals

* needed during embryonic development to form structures, organs and tissues (e.g. spaces between the digits, pruning unneeded nerve cells)

characteristics of apoptosis

* overall shrinkage in volume of the cell and its nucleus
* loss of adhesion to neighboring cells
* formation of blebs at the cell surface
* dissection of chromatin into small fragments
* rapid engulfment by phagocytosis

Necrosis

process of cell death which generally follows some type of physical trauma or biochemical insult

* considered a regulated and programmed death, but much less orderly in nature

Characteristics of necrosis

* swelling of both of the cell and its internal membranous organelles
* membrane breakdown
* leakage of cell contents into the medium
* resulting induction of inflammation

Apoptosis (programmed cell death)

1. active in the adult where about 10^10-10^11 cells dies every day

* elimination of cells with irreparable genomic damage
* elimination of cells no longer needed


2. reduced or elevated apoptosis is linked to several human diseases:

* cancer
* parkinson’s, alzheimer’s, and huntington’s diseases
* diabetes type 1

Apoptosis Extrinsic pathway (receptor mediated)

is initiated by external stimuli

* tumor necrosis factor is a common stimulus (TNF)
* TNF bounds to TNF receptors to recruit procaspases to the intracellular domain of the receptor
* procaspases convert other procaspases to caspases
* caspases activate executioner caspases, leading to apoptosis

Apoptosis Intrinsic pathway (mitochondria mediated)

is initiated by intracellular stimuli

* stimulated by irreparable genetic damage, viral infection, etc.
* proapoptotic proteins stimulate mitochondria to leak proteins, mostly cytochrome c
* once in the cytosol, cytochrome c forms part of a multiprotein complex called apoptosome, that also includes several molecules of procaspase-9
* release of apoptotic mitochondrial proteins irreversibly commits the cell to apoptosis