Signaling Mechanisms

Question 1

Endocrine

Answer 1

long distance, molecules secreted into circulation

example: secretion of polypeptides (thyrotrophic hormone) or steroids (estradiol)

Question 2

Paracrine

Answer 2

cells secrete molecules to neighboring cell

glucagon, somatostatin

Question 3

Autocrine

Answer 3

cell secrete molecules to themselves (prostaglandins)

Question 4

Messangers that bind to intracellular receptors

Steroids that bind to intracellular receptors

Answer 4

Estrogen
Progesterone
Testosterone
Corticosteroids (from adrenal medulla)

All of these are synthesized from cholesterol

Question 5

Non-steroids that bind to intracellular receptors

Answer 5

thyroid hormon (synthesized from tyrosine), vitamin D3, retinoids

Question 6

a family that contains a ligand binding site and are called the actual _____

Answer 6

nuclear receptor superfamily, consisting of thyroid hormone, vitamin D3, retinoids

transcription factors (regulators of DNA transcriptional activity)

Question 7

Nuclear receptor superfamily can do what

Answer 7

bind to intracellular receptors AND cross the membrane

Question 8

Neurotransmitters that bind to cell surface receptors

first

Answer 8

• acetylcholine
• peptides
• amino acids
  a. Aspartate
  b. Glutamate
  c. Glycine

    Gamma aminobutyric acid (GABA): requires    
    decarboxylation of glutamate

Question 9

Neurotransmitters that bind to cell surface receptors

second

Answer 9

Monoamines: amino acids that have been modified with minor changes. These include

catecholamines (derived from tyrosine)

• Dopamine
• Epinephrine
• Norepinephrine

Indoleamines (derived from tryptophan)
- Serotonin

these guys are hydrophilic, so they can’t pass through the cell membrane

Question 10

NON-neurotransmitter peptides that bind to cell surface receptors

Answer 10

insulin, glucagon, pituitary trophic hormones

Question 11

NON-neurotransmitters that bind to cell surface receptors

Answer 11

Growth factors

• Nerve growth factor
• Epidermal growth factor
• Platelet derived growth factor

Question 12

Downstream signaling molecules have a commonality

Answer 12

they all contain binding sites for phosphotyrosine peptides

SH2 domains were the first to be characterized
(initially identified in protein tyrosine kinases related to Src)

Binding of growth factors to extracellular domains activates their cytosolic kinase domains

Question 13

The cytosolic kinase domains of _______ are activated by ______ which ___ to their ________

Answer 13

Downstream signaling molecules which contain binding sites for phosphorotyrosine peptides

growth factors

bind to their ECM domains

Question 14

the cytosolic kinase domains of ________ become activated by growth factors, what happens next

Answer 14

DSM (downstream signaling molecules)

phosphorylation of receptor and target proteins that propagate the signal

first step is ligand induced receptor dimerization

leads to receptor autophosphorylation

Question 15

First two steps involved in activating cytosolic kinase domains

Answer 15

1. ligan-induced receptor dimerization

2. which in turn induces autophosphorylation

Question 16

Receptor associated molecules

Answer 16

G-protein coupled receptors
tyrosine kinases
cytokine receptors (JAK family or Src family)

Question 17

Tyrosine kinases

Answer 17

act as receptors
possess intrinsic kinase activity
activated by dimerization = leads to autophosphorylation

Question 18

Cytokine receptors

Answer 18

do not have kinase activity
associated with JANUS kinase family (JAK) or Src family
phosphorylated by cytosolic kinases

Question 19

Src

Answer 19

protein kinases “oncogenic protein of Rous sarcoma virus”

Question 20

protein tyrosine phosphates

Answer 20

enzyme linked receptor

Question 21

protein serine and threonine kinases

Answer 21

enzyme linked receptors: includes MAP kinases and TGF–beta receptors

Question 22

G couple protein receptors

i.e. receptors that bind to g proteins

Answer 22

Have 7 alpha helix domains

NH2 is the ECM, signal binding side, COOH is the ICM G protein interacting side

G proteins have three subunits (heterotrimeric): alpha, beta, gamma

Alpha unit is the most variable, has 20 different sequences, specific for a specific G protein

alpha subunit binds GDP when activated—> exchanges GDP to GTP

beta-gamma form dimer. 1

Question 23

G couple protein receptors: kinds

i.e. EFFECTORS

Answer 23

adenyl cyclase, phospholipases, ion channels

Question 24

Binding of ligand to a G protein-coupled receptor results in

Answer 24

exchange of GDP with GTP on an alpha subunit
dissociation of alpha subunit from the beta-gamma subunit
free alpha unit can act on specific effectors, or activate other G protein complexes to amplify initial signal

Question 25

the alpha subunit has _____ activity

Answer 25

GTPase: which is a self-limiting mechanism to reduce its effects effector stimulates GTPase activity in the alpha subunit

Question 26

G's: s, i, t-g, o, q

Answer 26

``` s = stimulates adenyl cyclase i = inhibits adenyl cyclase t-g = initiates breakdown of GMP in photoreceptors and taste receptors o = opens calcium ion channels in neurons q = activates phospholipases which increases IP3 activity ```

Question 27

FUNCTION of G couple proteins

Answer 27

g

Question 28

G protein couple receptor FUNCTIONS

Answer 28

1) Regulates enzymes 2) Regulates ion channels: i.e. acetylcholine receptor in heart muscle - inhibits adenyl cyclase beta-gamma activates potassium channels (keeps heart contracted longer) 4) Largest family responsible for odor detection 5) controls effectors which regulate secondary messenger activity (CAMP, which activates protein kinase A; DAG, which activates protein kinase C)

Question 29

Enzyme Linked Receptors

Answer 29

Single pass membrane receptor doesn't use an intermediary like G protein-coupled receptors do binds to an extracellular ligand which activates intracellular effector which generates an intracellular signal binding of ligand to ECM domain activates an enzyme or catalytic region which is an integral part of the intracellular domain

Question 30

Enzyme linked receptors succinctly stated

Answer 30

1. single pass transmembrane proteins 2. associate with effector on intracellular side that generates signal 3. doesn't use an intermediary like G protein 4. ligand binding on ECM domain activates catalytic region, integral part of the intracellular domain

Question 31

Enzyme linked receptors Classes

Answer 31

Receptors which possess guanylyl cyclase activity -increase intracellular cGMP concentration Receptors which catalyze "phosphorylation/dephosphorylation" of intracellular signaling proteins include Tyrosine kinase receptors Tyrosine kinase associated receptors Receptor tyrosine phosphates Receptor serine/threonine kinases

Question 32

Receptors which catalyze phosphorylation/dephosphorylation of intracellular signaling proteins

Answer 32

Tyrosine Kinase receptors Tyrosine Kinase associated receptors Receptor tyrosine phosphatases Receptor serine/threonine kinases

Question 33

Which receptors increase cGMP concentration

Answer 33

receptors which possess guanylyl cyclase activity

Question 34

Receptor Protein-Kinase Receptors Characteristics

Answer 34

a) directly linked to intracellular enzymes b) n terminal extracellular it has a single alpha helix ligand binding domain e) c-terminal is cytosolic with protein-tyrosine activity ligand-induced receptor dimerization receptor autophosphorylation

Question 35

C-terminal is

Answer 35

cytosolic with protein kinase activity

Question 36

Tyrosine Kinase: C- terminal autophosphorylation Inside Cat Domain/Outside Cat Domain

Answer 36

Inside cat domain causes an increase in protein kinase activity Outside cat domain creates binding sites for other proteins that transmit signal downstream

Question 37

Autophosphorylation of Tyrosine Kinase (2 scenarios)

Answer 37

Phosphorylation of catalytic site increases kinase activity Phosphorylation of non-catalytic site increases binding sites for other proteins that transmit signals downstream of the activated receptors

Question 38

Cytokine Receptors

Answer 38

Includes receptors for most cytokines a. interleukin-2 b. erythropoietin Cytosolic domains have no activity Cytosolic domains are associated with kinases such as JAK

Question 39

Cytokine Receptor Pathway: JAK-STAT

Answer 39

a. cytokines dimerize (caused by ligand reception) b. in turn cytokine dimer stimulates JAK c. JAK dimerizes d. JAK autophosphorylates e. Autophosphorylated JAK phosphorylates cytokine dimer f. cytokine dimer reveals phosphotyrosine binding sites g. supply binding sites for STAT h. STAT binds i. JAK phosphorylates STAT j. phosphorylated STAT forms dimer k. phosphorylated STAT translocates to nucleus and activate transcription

Question 40

STATs

Answer 40

Signal Transduction and Activator of Transcription different cytokine receptors activate different STATs different STATs up regulate different DNA sequences

Question 41

MAP/ERK pathway

Answer 41

``` Ras (GTPase) interacts with Raf Raf phosphorylates MEK (MAP or ERK) activated MEK phosphorylates ERK activated ERK translocates into the nucleus activated ERK phosphorylates ELK-1 ELK-1 interacts with SRE ELK-1+SRK form complex SRF ``` gene expression

Question 42

Ras, Raf, MEK, ELK, MAPK, MAP3K

Answer 42

Ras = GTPase Raf = MAP3K, a serine-threonine selective kinase MEK = MAP, ERK: tyrosine-threonine selective kinase ERK

Question 43

DAG is produced by

Answer 43

the PLC-gamma hydrolysis of PIP2

Question 44

the point of the PIP2 pathway is the

Answer 44

release of Ca2+

Question 45

5 steps in PIP2

Answer 45

1. signaling molecule binds and activate the protein kinase domains of a dimerized receptor 2. phospholipase C-gamma contains an SH domain that mediates its association with activated receptor protein tyrosine kinases 3. PLC-gamma catalyzes hydrolysis of PIP2, producing DAG 4. DAG activates protein kinase C 5. IP3 signals Ca2+ release

Question 46

W6

Answer 46

Linoleate cis, cis-triangle9, triangle 12 (2 double bonds) Arachdionate all-cis-triangle5, triangle8, triangle 11, -triangle14 (4 double bonds)

Question 47

w3

Answer 47

linolenate all-cis-triangle9, triangle12, triangle15 3 double bonds