Cell SignalingII

Question 1

Protein kinase associated membrane receptors

Answer 1

• Membrane receptors that directly transmit signals via phosphorylation of Intracellular protein targets(protein kinase receptor)
• The receptor is a kinase(activated upon ligand binding)
• 2 main types(receptor tyrosine kinase,receptor serine/threonine kinase
• many growth factors bind to protein kinase receptors
• important roles in cell proliferation,growth, and cancer

Question 2

Receptor Tyrosine kinase examples

Answer 2

• insulin receptor
• insuline-like growth factor-1(IGF-1)receptor
• nerve growth factor receptor
• epidermal growth factor(EFG) receptor

Question 3

Structure of receptor tyrosine kinase

Answer 3

-single polypeptide chain(may oligomerize upon ligand binding)
-single transmembrane domain
Extracellular portion-contain ligand binding domain
Intracellular portion-(tyrosine kinase domain, multiple tyrosine residues that can be autophosphorylated)

Question 4

Epidermal growth factor(EFG) receptor

Answer 4

• EFG binding site on Extracellular portion
• single transmembrane domain (single pass,synthesized at RER,ERSS and single internal stop transfer(c-terminus is in cytoplasm)
• tyrosine kinase domain and multiple tyrosine residues(at cytosolic tail) on the Intracellular portion

Question 5

Insulin like growth factor 1(IGF)

Answer 5

• 2 cross linked dimers(alpha and beta subunits)
• IGF-1 binding site on Extracellular portion
• single transmembrane domain for each dimer(ERSS and single internal stop transfer)
• tyrosine kinase domain and multiple tyrosine residues on the Intracellular portion
• encoded by a single gene and a single mRNA(the initial polypeptide is then glycosylated and cleaved into the subunits)

Question 6

EGF receptor activation function

Answer 6

Stimulate the growth repair, and proliferation of epithelial and mesenchymal cells and tissues

Question 7

EGF(ligand) binding results in?

Answer 7

1. Receptor aggregation(dimer)
2. the tyrosine kinases of the 2 receptors phosphorylate the tyrosine residues on the opposing receptor(autophosphorylation to form phosphotyrosine
3. following authophosphorylation,the cytosolic portion undergoes a conformational change that results in interactions with additional cytosolic signaling proteins

Question 8

EGF receptor signaling

Answer 8

1.the ligand(EGF) bind to the receptor(EGF receptor) and activates via dimerization and authophosphorylation
2.following activation, proteins that bind to phosphotyrosine can then interact with the receptor (these proteins have SH2 domains that binds phosphotyrosine)
GRB2-growth factor receptor-bound protein 2-activated Ras
3. Binds GTP via SOS
4.PLCgamma-to form DAG and IP3 from PIP2
5-7 following Ras activation(GTP binding)Ras initiates a series of phosphorylation steps
8.Ets and jun(along with fos)then promotes the expression of gene related to growth and mitosis
9.following signal termination,Ras is inactivated by GAPs(GTPase activating proteins)
The GAP facilitates GTP hydrolysis by Ras
Thus Ras is now bound to GDP and is inactive

Question 9

Following Ras activation(GTP binding),Ras initiates a series of phosphorylation steps

Answer 9

A)raf (mitogen activated protein kinase(3) MAPKKK.
B)mek (MAPKK)
C)MAPK
D)Ets(E twenty six,family of transcription factor
E)jun(early response transcription factor)

Question 10

Insulin stimulates what?explain

Answer 10

• stimulates glucose uptake into cells.
• The Insulin receptor (RTK), upon ligand binding and autophosphorylation, activates IRS-1 (insulin receptor substrate-1) via phosphorylation
• IRS-1 in turn activates PI3K, Akt (protein kinase B), → → elevation in glucose transporters in cell membrane via regulated secretion

Question 11

IGF stimulates what?

Answer 11

cell growth via activation of IRS-1, PI3K, Akt (protein kinase B), mTor, ribosomal synthesis and activity

Question 12

Differs RTKs activate..

Answer 12

Different cellular signaling pathways

Question 13

Receptor Serine Threonine Kinases (RSTK)

Answer 13

-Some growth factors utilize RSTKs to initiate intracellular signals
Ex:TGFb family of receptors
-Generally involve 2 types of receptors that function together
Type I and type II receptors (cooperatively bind the ligand, TGF or similar molecules like myostatin)
Both receptors are serine/threonine kinases
Send intracellular signals via the phosphorylation of R-Smad (receptor regulated Smad)
-R-Smads are a family of transcription factors

Question 14

TGFb family of receptors

Answer 14

Regulate a wide variety of cellular functions

Proliferation, apoptosis, cellular development & differentiation

Question 15

Process of thereonine/serine

Answer 15

-Prior to binding the ligand, the receptors (type I and II) are located individually at the cell surface(1. In the absence of TGF beta, the type I and II receptors TGFbeta are not clustered or phosphorylated. R-Smads and Smad4 are in cytosol.
-2. Binding of TGFbeta results in clustering of type I and II receptors, followed by phosphorylation of type I receptors by type II receptors
3-the activated type I receptor bind a complex of an anchoring protein and an R-Smad, resulting in R-Smad phosphorylation
-The phososphorylated R-Smad interacts with Smad-4 proteins and is translocated to the nucleus where it can influence gene expression in association with other transcription factors and co-regulators

Question 16

Myostatin

Answer 16

• TGFb family member
• Acts as a muscle growth inhibitor, secreted by muscle
• Knock out myostatin → elevated muscle growth.
• Occurs naturally:
  1. Double muscled cattle
  2. Mice
  3. Dogs
  4. Human

Question 17

Myostatin receptor

Answer 17

• activin receptor (RSTK)

- type I and II

Question 18

Functions of myostatin

Answer 18

1. Myostatin binds to the receptor
2. Causes phosphorylation of type I and then recruitment & phosphorylation of R-Smad
3. R-Smad enters nucleus with Smad-4
4. Changes in gene expression → suppress growth

Question 19

How do hormones exert such a wide variety of effect?

Answer 19

Epinephrine

Question 20

Epinephrine(adrenaline)

Answer 20

Hormone that stimulates a variety of cellular effects in different tissues (fight or flight response)

Question 21

How can epinephrine have such a diverse array of functions?

Answer 21

1. different receptors subtypes in different tissues
2. linked to different G-protein
3. and linked to different Intracellular signaling pathways and down stream targets

Question 22

Smooth muscle response to what?

Answer 22

Adrenegic stimulation

Question 23

Respiratory passage ways

Answer 23

• trachea, bronchi, bronchioles
• Have b2-adrenergic receptors
• Activate Gs→ ↑adenylyl cyclase activity, → ↑cAMP, → smooth muscle relaxation→ airway dilation (bronchodilation).

Question 24

Vasculature of (arteries & arterioles) skin, GI, kidney, brain

Answer 24

• Have a1-adrenergic receptors
• Activate Gq→ ↑PLC activity, → ↑IP3, → ↑ cytosolic [Ca2+] → smooth muscle contraction → vessel constriction → decreased blood flow.

Question 25

•Vasculature (arteries & arterioles) of skeletal & cardiac muscle

Answer 25

- Have b2-adrenergic receptors | - Activate Gs→ ↑adenylyl cyclase activity, → ↑cAMP, → smooth muscle relaxation→ vessel dilation → increased blood flow.

Question 26

Epinephrine effects on glycogen metabolism

Answer 26

1-cAMP bind to and activates protein kinase A 2-protein kinase A phosphorylates phosphorylase and activating it 3-active phosphorylase kinase phosphorylate phosphorylaseb, converting it to phosphorylase a, the active form of the enzyme 4-phosphorylase a catalyzes cleavage of a terminal glucose from glycogen as glucose 1-phosphate

Question 27

Adrenergic agonists (sympathomimetics)

Answer 27

- Phenylephrine (nasal decongestant) - Ephedrine (pseudoephedrine) - Clenbuterol, salbutamol (albuterol), metaproterenol, ractopamine (asthma treatments) - propranolol

Question 28

Phenylephrine (nasal decongestant)

Answer 28

- alpha1-adrenergic agonist (stimulates PLC and smooth muscle contraction) - vasoconstriction of nasal blood vessels, results in reduced blood flow to the nasal mucosa, relieves swelling of nasal mucosa

Question 29

Ephedrine (pseudoephedrine

Answer 29

- Same as phenyleprine, but also induces the release of noradrenaline - Stimulant actions (stimulates heart rate) result from direct and indirect activation of α- and β-adrenergic receptors (via noradrenaline release) - Actions on b-adrenergic receptors allow for airway dilation (bronchodilation) - Also used illicitly to manufacture methamphetamines

Question 30

Clenbuterol, salbutamol (albuterol), metaproterenol, ractopamine (asthma treatments)

Answer 30

- b2-adrenergic agonists (stimulate adenylyl cyclase and smooth muscle relaxation), allow for airway dilation (bronchodilation) - Also used to increase muscle mass, somehow activate the IGF-1 growth related pathway (at Akt)

Question 31

Propranolol

Answer 31

- Blocks the b receptors - Used for treating high blood pressure and heart pain (angina) and heart arrhythmia - Results in reduced blood pressure by 1. Reducing heart rate 2. Reducing the force of heart contractions