Lecture 15 - Signaling 2 Flashcards Preview

Unit 1 - Molecular and Cellular Principles of Medicine > Lecture 15 - Signaling 2 > Flashcards

Flashcards in Lecture 15 - Signaling 2 Deck (15):
1

What are the most common cell surface receptors?

1. Gated ion channels - impt for neuronal signaling 

2. Trimeric G-protein linked receptors control many metabolic fxns

3. Receptor tyrosince kinases - common for growth factors and often regulate choices b/n cell division and differentiation

2

Describe the differences between signaling by protein phosphorylation vs. by GTP-binding protein

Protein kinases add phosphates to regulate target proteins

Phosphates may be added to serine, threonine, or tyrosine

Phosphorylation can change confirmation, activity or binding affinity

Protein phosphates remove the phosphates to reverse regulation

 

G-proteins...

- slow GTPases that work as molecular ON/OFF switches

Protein confirmation changes when GTP is hydrolyzed

GTP bound confirm is "ON"

Hydrolysis of GTP > "OFF"

When "ON", G-proteins bind to and activate other enzymes

3

Monomeric vs trimeric G-proteins? 

Trimeric = alpha, beta, and gamma subunits

All known trimeric G-proteins associated w/ cell surface receptor signaling

Monomeric or small G-proteins receptor linked, others are involved in cellular processes

4

Describe the general pathway of G-protein coupled receptors

1. Receptors are 7-pass transmembrane proteins that bind extracellular ligands

2. Ligand binding stimulates interaction w/ trimeric G-protein and exchange of GDP for GTP on alpha subunit.

3. GTP binding causes dissociation of beta and gamma complex, from GTP bound alpha subunit - both modulate fxn of other proteins

4. Activated subunits are linked to membrane, but diffuse laterally and bind targets

5. Binding activates target (alpha and beta/gamma can both activate proteins.

6. Beta/gamma subunits dissociate from target and rebind w/ alpha, GTP is hydrolyzed, GDP binds to alpha

5

Describe the Gs family of G-proteins

Gs = stimulate adenylate cyclase

1. The activated cyclase makes cAMP faster, [cAMP] ^^^

2. cAMP diffuses throughout the cytoplasm and activates PKA (protein kinase A) whihc phosphorylates specific amino acid on substrate proteins.

6

How is PKA activated by cAMP?

1. PKA is inactive when regulatory subunits are bound

2. Each regulatory subunit has two cAMP binding sites

3. When cAMP is bound to the regulatory subunit, the catalytic subunits are released in active form (go on to phosphorylate other messangers)

7

Does cAMP bind direclty to transcription factors?

No it does not!

8

Describe the Gi-linked family of G-proteins

Gi-linked receptor activation inhibits adenylate cyclase

Leads to reductions in cAMP

Activation of Gi receptor can reverse effects of Gs receptor

9

Describe the Gq family of trimeric G-proteins

1. Ligand binds, actives Gq-protein, which activates phospholipase C

2. Activated phospholipase C generates IP3 (inositol triphosphate) and DAG (diacylglycerol).

3. IP3 binds to gated channels in the ER and releases Ca2+

4. Ca2+ both activates PKC, and calmodulin which activates CAM kinases

5. DAG also activates PKC by increasing its affinity for Ca2+

10

Describe the basic mechanism of tyrosine kinase receptors

1. Binding of a ligand (usually a growth factor) induces receptor dimerization, which results in transphosphorylation (each receptor molecule phosphorylates tyronsines on its partner)

2. When other proteins in the cell bind ot the phosphotyrosines, their confirmation changes and they pass the signal on. These proteins are called SH2 domains. 

11

What are some of the secondary messanger pathways involved with tyrosine kinases?

1. Binding stimulates phospholipase C-gamma, which activates IP3 and DAG pathways

2. SH2 domains of SH2-SH3 adaptor proteins bind and activate Ras monomeric G-protein pathway

Monomeric g proteins are activated by GTP exhange factors (GEFs) and turned off by GTPase activating proteins (GAPs)

12

Describe the cascade that Ras induces

GTP-bound Ras activates the MAP kinase cascade. Leads to cascade of phosphorylation and ultimately changes in protein activity and gene expression

13

Why should we care about the large # of families of tyrosine kinases?

At least one member of most of the families has been implicated in human malignancies. 

14

Describe JAK-STAT (as an example of tyrosine-kinase linked receptors)

JAK-STAT signaling activates gene transcription

Tyrosine transphosphorylation causes phosphorylation of JAK which phosphorylates STAT gene regulatory protein

This (along w/ other gene reg proteins) transcribed target DNA

15

Are these pathways independent from one another?

No, they're incredibly convoluted and involved w/ one another.