Receptor Tyrosine Kinases Flashcards Preview

HMS Chemical Biology and Biochemistry > Receptor Tyrosine Kinases > Flashcards

Flashcards in Receptor Tyrosine Kinases Deck (32)
1

Functions that RTKs tend to regulate

Growth, proliferation, differentiation, apoptosis

2

RTK ligands are usually. . .

proteins

3

GPCR ligands are usually. . .

small molecules

4

Basic structure of a receptor tyrosine kinase

Extracellular ligand binding domain

Transmembrane helix

Intracellular kinase domain

5

How is the signal of ligand binding tranduced across the membrane by RTKs?

By dimerization and transphosphorylation of the cytoplasmic kinase domains.

 

Note that this means, practically by definition, that substantial upregulation of these domains will lead to ligand-independent activation.

6

RTK dimerization loop

Domains on the extracellular side of the protein that dimerize to facilitate bringing together the intracellular domains of the RTKs.

7

Insulin receptor family-RTKs are. . .

pre-dimerized on the extracellular side

 

Binding just moves the cytoplasmic regions closer together so that they may interact by making the angle between them more acute.

8

FGFR family-RTKs. . .

multimerize along a carbohydrate chain (specifically heparan sulfate)

 

This heparan sulfate is often attached to a protein forming heparan sulfate proteoglycan (HSPG).  This also serves to localize the signal.

9

Difference between the terms "cross-phosphorylation" and "auto-phosphorylation"

"cross-phosphorylation" refers specifically to the phosphorylation of one receptor by another

 

Autophosphorylation may refer to self phosphorylation or to cross-phosphorylation.

10

Activation loops on RTKs

11

How does cross-phosphorylation lead to downstream effects?

Cross-phosphorylation enables the kinase domains to phosphorylate multiple sites on the juxtamembrane domain of the receptor.  These sites, when phosphorylated, serve as docking sites for other proteins, such as GRB2.  The active kinase domains may also, of course, phosphorylate other proteins to propagate the signal, and some of this activity is mediated by these docking site which serve a recruitment role for substrates.

12

Common domains in RTK signal propagation

13

Although all SH2 domains recognize phosphotyrosine, . . .

they also recognize adjacent amino acids.  

 

This is true for almost all of these binding domains, they are slightly different in order to control specificity.

14

Ras

15

Grb2

16

MAPK Cascade

"Mitagen Associated Protein Kinase"

17

KSR Scaffold

18

MAPK Cascade downstream effects

19

Ras is a _____ G protein.

monomeric

20

PI3K recruitment

21

Reaction Catalyzed by PI3K

22

PI3K Activation of Akt/PKB

23

PDK1

Recruited to the PM by PIP3

 

Phosphorylates and stably activates Akt when it is brought into proximity.  Akt is then active and may diffuse into the cell to exert its effects.

24

Major Akt targets

BAD and Caspase 9 are proteins that mediate apoptosis, otherwise known as programmed cell death

FOXO is a transcription factor that upregulates expression of pro-apoptotic genes.

Inhibition of certain GAPs leads to increased GLUT4 insertion into the membrane and thus increased glucose uptake.

25

mTOR

mTOR is a regulator of protein synthesis. The best characterized way it does that is by phosphorylating a protein called 4E-BP. In its unphosphorylated state, 4E-BP binds and inhibits the initiation factor eIF4E (an initiation factor that binds the mRNA cap). Because 4EBP inhibits eIF4E, and mTOR inhibits 4E-BP, the net effect is that mTOR promotes translation.

26

AMP Kinase

AMP kinase responds to the AMP/ATP ratio in the cell. When the AMP/ATP ratio is high, that activates AMP kinase, which phosphorylates and activates TSC2.

Since TSC2 is a GAP for Rheb, that inactivates Rheb, and the net effect is to inhibit translation when energy stores are low:

if the cell is running out of energy, it doesn’t want to be using the large amount of energy needed to make a protein.

 

Note that phosphorylation of TSC2 by AMPK activates it, whereas phosphorylation by AKT at different sites inactivates it, and that’s how these two inputs can have opposite effects on translation.

27

Turing off RTKs

28

Protein Tyrosine Phosphatases (PTPs)

29

PTEN

Dephosphorylates PIP3

30

HER-family RTKs

Her1 = EGFR

31

Her2

Her2 has no known ligand. However, even without a ligand Her2 is in a conformation that allows it to dimerize: either homodimerizing with itself, or by forming heterodimers with other members of the Her family.

 

Its activation loop doesn’t need to be phosphorylated to be in the open state: kinase domain dimerization triggers a conformational change that is sufficient to open up the loop and make the kinase catalytically active

32

Her3

Her3 has an inactive kinase. It actually does have a full length intracellular region, but the kinase domain lacks catalytic activity