part 4 of day II Flashcards
Receptors that are kinases
serine/threonine kinase receptors
TGF-beta signaling
Binding of TGF-beta (a type of cytokine) alters the receptor so it can bind to a second receptor and phosphorylate it at serine/threonine residues.
The second receptor is then able to bind a protein, R-Smad, and
How do plasma membrane receptors transmit signals?
How do signaling pathways change gene expression?
phosphorylate it
TGF-beta signaling
1) TGF-Beta binds to type II receptors
2) Type II receptor phosphorylates type I receptors
3) activated type I receptor phosphorylates R-Smad
4) R-Smad complexes with Cp-Smad and migrates to the nucleus
The phosphorylation of R-Smad allows it to interact with a Co-Smad protein.
R-Smad
regulatory Smad
Receptors that bind to and activate kinases
Jak-Stat signaling
unlike other receptors, these receptors are not kinases
Jak-Stat signaling
Binding of a cytokine activates the receptor to dimerize and bind Jak proteins, which are then activated to phosphorylate each other and the receptor
Stat proteins then bind and are phosphorylated by Jak proteins. This triggers the Stats to dissociate from the receptor and dimerize.
The dimerized Stats move to the nucleus, bind to genes, and alter their rate of transcription
Jak-Stat signaling
detail
1) receptors bind cytokines, dimerize, and bind JAKs
2) JAKs phosphorylate each other and the receptors
3) Receptors binds and phosphorylates STATs
4) STATs dissociation from receptors, dimerize, translocate to nucleus
Jak-Stat signaling
drug target
Inhibitors of the Jak kinases are approved for the treatment of
psoriasis, myelofibrosis, and rheumatoid arthritis.
Jak-Stat signaling is abnormally activated in some cancers. Jak inhibitors are being evaluated in clinical trials for treatment of leukemia and Stat inhibitors are under development.
Heptahelical or G-protein-coupled receptors (GPCRs)
GPCRs have 7 membrane-spanning, a-helices.
They associate with heterotrimeric (3 subunit-a,b,g) G-proteins in
How do plasma membrane receptors transmit signals?
the absence of their ligand.
GPCRs are bound by
There hundreds of different GPCRs that are specifically bound by hundreds of hormones or neurotransmitters.
Examples: Epinephrine, serotonin, eicosanoids (prostaglandins, leukotrienes), histamine, glucagon
Heptahelical or G-protein-coupled receptors (GPCRs)
response
Binding of the ligand to the receptor triggers a cellular response through changes in production of second messengers.
What is a second messenger
A second messenger is a small, diffusable signaling molecule, the production of which is altered in response to a stimulus. They regulate effector proteins within the cell to exert a cellular response.
Examples: cAMP, cGMP, diacylglycerol (DAG), inositol triphosphate (IP3), calcium ions, nitrous oxide (NO)
Different GPCRs
Different GPCRs associate with distinct G-protein complexes which differ in their alpha subunit.
- Different alpha subunits regulate the production of different second messengers
Ga(s) – increases cAMP production
Ga(i/o) – inhibits cAMP production
Ga(q/11) – increases DAG, IP3, and calcium
example: GPCR bound to a G protein complex with Ga(s)
1) The G protein complex breaks apart and away
from the receptor upon binding of ligand
2)The alpha subunit exchanges its bound GDP for GTP
3) The GTP-bound Ga(s) binds adenylate cyclase and activates it to make cAMP.
4) Eventually Ga(s) hydrolyzes the bound GTP to GDP, inactivates itself, and reassociates with receptor and the b,g subunits.
What happens to the second messenger
Once the second messenger is produced it diffuses through the cytoplasm and binds specific proteins.
Example: cAMP signaling
cAMP binds Protein Kinase A (PKA) and
activates it
PKA phosphorylates transcription factors and activates them to bind genes and alter their transcription.
Key concept of what happens to the second messenger?
Key concept: Proteins bound by second messengers alter gene expression through regulation of transcription factors.
