10.3 Enzyme-coupled receptors

2 types of enzyme-coupled receptors

1. have their own enzyme activity

2. associate with another enzyme

4 types of extracellular signals that bind to enzyme-coupled receptors

1. growth factors

2. growth hormones

3. insulin

4. cytokines

5 types of growth factor extracellular signals

1. Insulin-like (IGF)

2. Epidermal (EGF)

3. Platelet-derived (PDGF)

4. Fibroblast (FGF)

5. Nerve (NGF)

Growth, proliferation, differentiation, survival of cells

• extracellular signals are growth factors

• slow cellular response to enzyme-linked receptors

• changes in gene expression occurs

Changes in cytoskeleton

• rapid cellular response to enzyme-linked receptors

• extracellular signals are proteins attached to surfaces over which a cell is crawling

Receptor tyrosine kinases

• largest class of enzyme-coupled receptors

• has single transmembrane segment

  • Poorly suited to transmit a conformational change across the membrane

Dimerization

• process caused by extracellular signal binding to RTK

• results in two RTKs to link

• activates kinase activity within receptor tails

Phosphorylation

• process that dimer tails does upon one other

• occurs on specific tyrosine residues

Docking sites

purpose of newly phosphorylated tyrosines for other intracellular signaling proteins

Ras

• monomeric GTP-binding protein associated with the membrane

• protein mostly indirectly activated by RTKs

• directly activated by Ras-GEF

• with a covalently attached lipid group for attachment to the inner plasma membrane

Mutant Ras

• protein mutation involved in human cancers

• exhibits no GTPase activity

• cannot hydrolyze its bound GTP to be inactivated

• promotes uncontrolled cell proliferation

Oncogene

• type of mutated Ras gene

• promotes uncontrolled cell proliferation and development of cancer

6 steps of activation of Ras by RTK

1. RTK activated

2. adaptor protein docks to specific phosphorylated tyrosine

3. Ras guanine nucleotide exchange factor (Ras-GEF) recruited by adaptor protein

4. Ras-GEF exchange GDP into GTP to activate Ras

5. GTP-activated Ras initiate multiple
   downstream signaling pathways

Guanine nucleotide exchange factors (GEFs)

• promote exchange of bound GDP for GTP

• switches on the GTP-binding protein like Ras

GTPase-activating proteins (GAPs)

• stimulate hydrolysis of GTP to GDP

• switches off the GTP-binding protein like Ras

MAP-kinase cascade

initiated phosphorylation cascade by GTP-activated Ras

Mitogens

extracellular signal molecules that stimulate cell proliferation

5 steps in the MAP-kinase cascade

1. Raf (MAPKKK) activated by GTP-activated Ras

2. MEK (MAPKK) phosphorylated by active Raf

3. ERK (MAPK) phosphorylated by active MEK

4. transcription regulators phosphorylated by active ERK

5. control over cell proliferation, survival, and differentiation

Protein tyrosine phosphatases

• involved in termination of RTK response

• protein that dephosphorylates added group to RTK dimer tails and other involved intracellular signaling proteins

Endocytosis

• termination of RTK response

• receptors are destroyed by digestion in lysosomes

Phosphoinositide 3-kinase (PI 3-kinase)

enzyme activated by RTK to promote cell growth and survival

6 steps in activation of PI-3-kinase-Akt signaling pathway

1. extracellular survival signal (eg. IGF) activates RTK

2. PI 3-kinase recruited and activated by RTK

3. inositol phospholipid phosphorylated by PI 3-kinase to be docking sites

4. protein kinase B (Akt) docks

5. Akt is phosphorylated and activated by kinases

6. Activated Akt is released from plasma membrane and phosphorylates various intracellular signaling proteins

Protein kinase B (Akt)

• serine/threonine protein kinase

• promotes growth and survival of cell types

• inactivates signaling proteins by phosphorylation

5 steps of Akt in cell survival

1. Bad phosphorylated by AKt

2. Bad rendered inactive

3. active Bcl2 released

4. cell survival promoted

Bcl2 VS Bad

Bcl2: suppresses apoptosis

Bad: unphosphorylated form inhibits the Bcl2; promoted apoptosis

5 steps of Akt in cell growth

1. growth factor bind to RTK

2. PI-3-kinase-Akt signaling pathway activated

3. Tor shutdown protein is phosphorylated by Akt

4. Tor activated

5. Tor stimulates protein synthesis and inhibits protein degradation

Tor

• large serine/threonine kinase

• stimulates cell growth

• enhances protein synthesis and inhibiting protein degradation

Rapamycin

• anticancer drug

• slows cell growth by inhibiting Tor