Signal Transductions/Cell signaling pathways

Question 1

Extracellular messengers

Answer 1

-Small molecules such as amino acids
-Gasses such as NO and CO
-Steroids
-Arachidonic acid derivatives
-Various peptides and proteins

Question 2

Steroids (cell signaling)

Answer 2

Steroids are synthesized from cholesterol, are NON polar, and bind to intracellular receptors. They can diffuse freely through membranes. Structure is 4 carbon ringed core. Receptor/hormone complexes move to the nucleus and act as transcription factors

Question 3

Cell surface receptors sometimes
generate an intracellular second
messenger through an enzyme
called an

Answer 3

Effector, small substances that activate (or
inactivate) specific proteins.

Question 4

Signal transduction

Answer 4

Protein confirmation is usually altered by phosphorylation, Kinases add phosphate groups while phosphatases remove them.

Question 5

Signals require an integral membrane protein receptor. These receptor families include…

Answer 5

GPCRs - G protein coupled receptors
RTKs - Receptor tyrosine kinases

Question 6

GPCR’s

Answer 6

Largest super family of proteins. GPCRs have 7 alpha-helical transmembrane domains and interact with heterotrimeric G proteins, on the cytoplasmic side. Its natural ligands are hormones, neurotransmitters, opioids, and chemoattractants. the binding to any of these changes its confirmation. Which in turn, could lear to signaling cascades. They have their amino terminal on the outside of the cell, and the C terminal on the inside.

Question 7

What are the 4 types of Herotrimeric G proteins

Answer 7

Gq - members contain Galpha subunits that activate PLCbeta
Gs - members couple receptors to adenylyl cyclase
Gi - function by inhibiting adenylyl cyclase
G12/13 - less well characterized

Question 8

GPCR-Gαq-PIP2-PLC-IP3-DAG-PKC pathway

Answer 8

begins with GPCR molecule, associated with Gaq protein. (3 subunits) Alpha subunit is bound to a GDP molecule. This is the inactive state.
-When a signaling molecule comes along and binds, the alpha subunit swaps its GDP for a GTP, and the beta and gamma subunits detach.
-The activated G-alpha subunit binds to phospholipase C (enzyme), and the PLC active site is revealed and can bind to its substrate. —-The substrate is cleaved leaving the DAG in the membrane, and IP3 in the cytoplasm.
-IP3 wants to get to the ER, so it binds to the ER IP3 gated Ca2+ release channel, and releases all the Ca2+ from the lumen into the cytoplasm.
-DAG binds to Protein Kinase C and Ca2+ to become activated.

Question 9

GPCR-Gas -AC-cAMP-PKA signaling pathway

Answer 9

begins with GPCR molecule, associated with Gas protein. (3 subunits) Alpha subunit is bound to a GDP molecule. inactive state.
-When a signaling molecule comes along and binds, the alpha subunit swaps its GDP for a GTP, and the beta and gamma subunits detach.
-Main target for G-alpha subunit is an enzyme called adenylate cyclase (AC) (a membrane protein that catalyzes the rxn of ATP into cyclic AMP)
-G-alpha subunit interacts with AC to activate it, and AC starts making lots of C-AMP. (Cyclic AMP is not usually found in the cell. when it shows up, this means there is something going on outside of the cell.)
-In the cell, C-Amp targets Protein Kinase A, 4 C-Amp bind to the 2 regulatory subunits of PKA. The regulatory subunits and catalytic subunits of PKA dissociate from each other.
-The catalytic subunits, kinases, can phosphorylate target proteins
- PKA can move into the nucleus and activate CREB which can turn on or off gene transcription (long lasting effects)
How is this pathway inactivated??
-Ligand removal
- GTP hydrolysis
- breakdown of C-Amp by phosphodiesterase enzyme
-activation of GRK by overstimulation, arrestin.

Question 10

GPCR - Gai signaling pathways

Answer 10

This pathway, Gai, is the inhibition of the Gas pathway.
GPCR molecule, associated with Gai protein. (3 subunits) Alpha-i subunit is bound to a GDP molecule. inactive state.
-When a signaling molecule comes along and binds, the alpha-i subunit swaps its GDP for a GTP, and the beta and gamma subunits detach.
-The alpha-i/GTP subunit can then associate with AC.
-AC can then no longer associate with the G-alpha s subunit, and it is released.
An example of this process is regulation of cardiac muscle contraction

Question 11

Receptor Tyrosine Kinase (RTK)

Answer 11

often associated with receptors for growth factors, They can regulate the receptors Kinase activity, or they can serve as binding sites for cytoplasmic signaling molecules.Single membrane spanning domain.

Question 12

MAP kinase signaling
pathway with Ras/ Raf/ MEK/ Erk

Answer 12

pathway involved in cell proliferation, growth and differentiation
-RTK monomers bind to each other in the presence of a signal. Dimerized receptor.
-The individual monomers reach across and phosphorylate each others Tyrosine residues. Becomes Activated.
-Protein called GRB 2 binds to a phosphorylated tyrosine residue. GRB2 then recruits Son of sevenless (SoS) to the gang.
- SoS interacts with a small monomeric G protein called Ras, which is tethered at the membrane. Ras drops its GDP, picking up a GTP, and becoming activaed.
-Protein Raf (MAP 3K) binds to Ras/GTP and becomes phosphorylated.
-Then, activated Raf can phosphorylate MEK (MAP 2K)
-Then, activated MEK can phosphorylate ERK (MAPK)
-Activated ERK can then phosphorylate a variety of targets. Also can translocate into the nucleus.
Ras is linked to 30 types of cancer. 17% of cancer patients have a mutation in Ras.

Question 13

Insulin Receptor and P13K-Akt signaling pathways

Answer 13

• Insulin binds to an Insulin receptor (alpha and beta subunits), where there is a confirmational change, and the cytoplasmic parts are drawn close together where they phosphorylate one another. Receptor is now ON.
  -Scaffolding protein, Shc binds to phosphotyrosine, where it is phosphorylated and then can bind GRB2 and SoS; activating the Ras MAP Kinase signaling pathway.
  -once the Insulin receptor is phosphorylated, it can bind the Insulin receptor substrate to the phosphotyrosine, where it is phosphorylated.
  -Once IRS is phosphorylated, PI3K is recruited to the membrane (PI3K is an enzyme that catalyzes the phosphorylation of PIP2-PIP3. PIP3 is NOT normally found in the cell.
  -PDK1 and AKT can be recruited to and bind to PIP3 through membrane, PDK1 is activated phosphorylates AKT.
  (If Akt is ALSO phosphorylated by mTORC2, THEN it becomes fully activated)

Question 14

Where is Insulin synthesized? How does it function?

Answer 14

Cells in the pancreas. It gets released when glucose levels are high. It functions as an extracellular messenger.