Enzyme-Linked Cell surface Receptors

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Left is FAST

Right is SLOW

What is the main effective difference in these two signaling mechanisms?

G protein-linked Receptor

This is an example of what?

Ion-channel-linked receptor

This is an example of what?

Enzyme-linked receptor

This is an example of what?

Ca2+ release

PKC activation

IP3 leads to what ?
DAG leads to what?

tyrosine residue

Depending on which ____________ gets phosphorylated, a RTK can have different downstream signalling effects.

Ligand binding initiates receptor dimerization
• Phosphorylate the adjacent receptor (tyrosine residues)
• Signaling molecules are recruited

What 3 things are happening here?

Recognize phosphate group at receptor

Recognize phosphate group at lipid membrane

Recruits accessory proteins; does not bind to phosphate

What is the Role of SH2 and PTB?

What is the role of PH?

What is the role of SH3?

Receptor Tyrosine Kinase (RTK)

Activate Ras; when it binds to GTP

Insulin!!!!!

What is this? What is one important thing it can do?

What it an IMPORTANT example of this?

Serine/Threonine kinase domains activate SMAD

Travels to nucleus and activates transcription

1) Binding of the ligand induces
dimerization.
2) Serine/threonine are
phosphorylated
3) Activation of SMAD
by phosphorylation
4) SMAD oligomerize
and regulate gene expression.

What is going on here?

What does SMAD do?

MAP-Kinase Cascade (mitogen-activated protein kinase)

Active Ras

What is this called?

What causes a MAP cascade?

Signal pathways are very interconnected

What does this illustrate?

GPCR (trans-membrane, alpha, beta)

What is an example of a trimeric G protein?

TRK (dimerizes to become active)

What are examples of monomeric G proteins?

INACTIVATES Ras; Activates Ras GTPase activity, causing GTP to be hydrolyzed; Ras-GAP keeps most of the Ras inactive

GEF ACTIVATES Ras; Causes Ras to eject GDP, so that it can binds free GTP

Inability to hydrolyze GTP, thus it would be constitutively active! Increasing cell proliferation

What does Ras-GAP do?

What does Ras-GEF do?

What would a mutation of Ras lead to?

Turns GTP to cGMP

Ligands are usually peptide hormones

What does guanylate cyclase do?

Soluble Guanylyl cyclase

Rapid smooth muscle cell RELAXATION

Nitroglycerides

cGMP phosphodiesterase-V (PDE-V) that inactivates cGMP

What does NO activate?

What is the effect?

What is a medication that increases NO?

What does Viagra work on?

Tyrosine Kinase Receptor

Insulin bind to α subunit

Causes β subunits to autophosphorylate

The Activated ITRK then acts on targets such as Insulin Receptor Substrate-1 (IRS-1)

What type of receptor is the insulin receptor?

Insulin binds to ______? Causes what to happen?

SH2

IRS family proteins interact with other cellular proteins via their ___________ domain

Metabolism is short acting
Growth is long acting

What is short acting?
What is long acting?

Phospholipase C (PLC) activates protein phosphatases; REGULATES Lipid and Glycogen Synthesis

PI-3 kinase; Insertion of GLUT4 receptors

MAPK; modulates Gluconeogenesis and glycogenolysis via gene expression

What are the three insulin pathways?

Muscle and Adipose tissue

Where does this happen?

PI-3-K in the LIVER

FKHR → Gluconeogenesis ↓

GSK3 → Glycogen Synthesis ↑

mTOR → Protein Synthesis ↑

JNK (SREBP, PGC) → Lipid Lipoprotein homeostasis and lipogenesis ↑

Which pathway is this and where does it happen?

What does each orange oval effect?

Insulin inhibits the expression of PEPCK, the RATE-LIMITING step of gluconeogenesis

Glucagon

Ras/MAPK pathway

Prevents AF2 from binding and activating PEPCK gene

Insulin inhibits the expression of the gene for what protein?

It is opposed by which signaling factor?

Which pathway mediates this effect of insulin?

What does IREB do?

PEPCK↓ → Gluconeogenesis inhibited

GAPDH↑ Glycolysis is stimulated

Insulin has these effects on these enzymes. What is the result?

Insulin Responsive Element (Transcription factor)

PEPCK Gluconeogenesis

GAPDH (GA-3-PDH) Glycolysis

What is an IRE?

What two important genes are modified by IREs?

Protein Kinase A

Fructose 2,6 bisphosphatase

Shuts off gluconeogenesis

Glucagon

What two things does insulin cause to be dephosphorylated? What effect does this have?

What signaling factor opposes insulin here?

Stimulating Glycogen Synthase (B)

Inhibiting Glycogen Phosphorylase (A)

What two Enzymes is Insulin acting upon (A and B)?

Membrane-bound

Intracellular

What are the two types of guanylate cyclase?

Protein Kinases that Phosphorylate

Protein Phosphatases that Dephosphorylate

Insulin regulates growth via protein ____________ that __________

Insulin regulates metabolism via protein ______________ that _______________

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