RTK and signaling through RAS

Question 1

What are the 2 main protein kinases?

Answer 1

• Serine/Threonine: they phosphorylate the hydroxyl groups of serines and threonines in their target
• Tyrosine kinase: Phosphorylate proteins on tyrosines

Question 2

Explain the GTP-GDP molecular switch

Answer 2

Cell signaling is on when GTP is boud. In order to inactivate the switch: GAP is needed to phosphorylate GTP into GDP. Now there is no cel signaling. In order to activate the switch again, GEF will remove GDP so a new GTP molecule can bind

Question 3

What is the function of a scaffold protein

Answer 3

Scaffold proteins bring together groups of interacting signaling proteins into signaling complexes

Question 4

Explain the insulin signaling pathway with the proteins IRS1, Grb2 and SOS

Answer 4

If Insulin ligand binds to receptor: the activated receptor will phosphorylate itself on tyrosines, and 1 of the phosphorytyrosines then recruits a docking protein (IRS1) via a PTB domain of IRS1. The PH domain of IRS1 also binds to a specific phosphoinositides on the membrane. Then, the activated receptor phosphorylates IRS1 on tyrosines, and 1 of these phosphorytyrosines binds the SH2 doamin of Grb2. Next, Grb2 uses 1 of her SH3 domains to bind a proline-rich region of SOS what relays the signal downstream by acting as a GEF. Grb2 uses her other SH3 domain to bind to a proline-rich region in scaffold domain which will bind several other signaling proteins

Question 5

Explain the dimerizing RTK proteins

Answer 5

Ligand binding causes the receptors of RTK to dimerize (bringing 2 kinase domains together). In absence of the extracellular signals: RTK’s as monomers aka an ia state. Binding of the ligands bring 2 monomers together to form a dimer. The dimers will then phosphorylate each other for activation

Question 6

What are the steps of RAS-MAPK pathway?

Answer 6

RTK monomers form a dimer, after phosphorylation, those monomers gets activated. SH2 domain of Grb2 domain will bind to a phosphore. The SOS protein (Ras-GEF) will bind to the SH3 domains. Ras-GEF will help activating RAS protein which will then phosphorylate Raf. Raf then will phosphorylate Mek and Mek will phosphorylate Erk.

Question 7

Explain the PI3K-Akt pathway and its function

Answer 7

An extracellular survival signal activates an RTK, which activates PI-3 kinase, this will produce PIP3, which serves as a docking site for 2 serine/threonine kinases with PH domains. Those 2 go to plasma membrane. The Akt is phosphorylated on a serine by 3rd kinase (mTOR) –> conformation of Akt so it can be phosphorylated on a threonine by PDK1 which activates Akt. Akt can phosphorylate Bad protein. When Bad is unphosphorylated: Bad holds Apoptosis inhibitory proteins in an IA state. Once phosphorylayed: Bad releases the inhibitory proteins which now can block Apoptosis and thereby promote cell survival.

Question 8

What protein is in control of the PI3K-Akt pathway?

Answer 8

TOR