Mechanisms for Down-Regulating the Cell Cycle: Regulating Receptors and Initiating S Phase | Study notes Biology

3-26-10

RTK III: Mechanisms to Down-regulate

Making S Phase Cytoplasm

Mechanisms for Down-Regulation of the Cell Cycle

1. Receptor unbinds from the ligand

a. Depends on the concentration of the ligand (a lower concentration causes unbinding)

2. Digestion of receptors by proteasomes

a. Cbl is a ubiquitin ligase and is able to bind to both dimerized receptors on their

phosphorylated tyrosine residues near the membrane. Cbl then adds ubiquitin to the

receptors and causes them to be digested by 26S cytoplasmic proteasomes.

3. Dephosphorylate tyrosine residues on the receptors

a. Phosphatases present in the smooth ER can dephosphorylate the receptors. Then

molecules like PlCγ and GRB2 wouldn’t be able to bind to the receptors and move the

cell cycle forward.

4. Endocytose the receptors for digestion

a. Send receptors to the lysosome; decreases the number of receptors at the surface

5. Slow ras GTPase activity

a. GRB2 binds to SOS which activates ras. The GTPase in ras will eventually hydrolyze GTP

to GDP and inactivate the ras molecule

6. Faster ras GTPase activity

a. rasGAP can bind to phosphorylated tyrosines in receptors and speed up the GTPase

activity in ras molecules to inactivate them.

7. Inhibit raf activation by a high cAMP concentration

a. A high concentration of cAMP inhibits raf activation and keeps the cell in G1

8. Cut the receptor into pieces

a. Enzymes called regulated intramembrane proteases (RIPs) present in the membrane can

cut the receptors directly outside or directly inside the membrane and prevent its

correct function. The inner portion of the receptor has a NLS, so it can then enter the

nucleus.

These mechanisms help to avoid transformation into cancer cells.

Making S Phase Cytoplasm

MAP kinase phosphorylates TCF four times inside the nucleus and causes the molecule SUMO to

fall off. TCF then transcribes the c-fos gene, making c-fos mRNA that enters the cytoplasm and is

translated into fos protein.

Fos protein has a protein partner jun that is already present in the cytoplasm (jun is already

phosphorylated once). Jun binds to fos to form a fos-jun heterodimer.

MAP kinase then phosphorylates the fos-jun heterodimer (once on each molecule).

The phosphorylated heterodimer is also known as AP1. AP1 is a transcription factor that re-

enters the nucleus and binds to the promoter of the c-myc gene, which it then transcribes.

The c-myc mRNA leaves the nucleus and is translated into c-myc protein in the cytoplasm. The

c-myc protein also has a protein partner, MAX, in the cytoplasm.

C-myc binds to MAX to form a heterodimer and is also phosphorylated by MAP kinase (once on

each molecule).

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RTK III: Mechanisms to Down-regulate Making S Phase Cytoplasm Mechanisms for Down-Regulation of the Cell Cycle

Receptor unbinds from the ligand a. Depends on the concentration of the ligand (a lower concentration causes unbinding)
Digestion of receptors by proteasomes a. Cbl is a ubiquitin ligase and is able to bind to both dimerized receptors on their phosphorylated tyrosine residues near the membrane. Cbl then adds ubiquitin to the receptors and causes them to be digested by 26S cytoplasmic proteasomes.
Dephosphorylate tyrosine residues on the receptors a. Phosphatases present in the smooth ER can dephosphorylate the receptors. Then molecules like PlCγ and GRB2 wouldn’t be able to bind to the receptors and move the cell cycle forward.
Endocytose the receptors for digestion a. Send receptors to the lysosome; decreases the number of receptors at the surface
Slow ras GTPase activity a. GRB2 binds to SOS which activates ras. The GTPase in ras will eventually hydrolyze GTP to GDP and inactivate the ras molecule
Faster ras GTPase activity a. rasGAP can bind to phosphorylated tyrosines in receptors and speed up the GTPase activity in ras molecules to inactivate them.
Inhibit raf activation by a high cAMP concentration a. A high concentration of cAMP inhibits raf activation and keeps the cell in G
Cut the receptor into pieces a. Enzymes called regulated intramembrane proteases (RIPs) present in the membrane can cut the receptors directly outside or directly inside the membrane and prevent its correct function. The inner portion of the receptor has a NLS, so it can then enter the nucleus. These mechanisms help to avoid transformation into cancer cells. Making S Phase Cytoplasm  MAP kinase phosphorylates TCF four times inside the nucleus and causes the molecule SUMO to fall off. TCF then transcribes the c-fos gene, making c-fos mRNA that enters the cytoplasm and is translated into fos protein.  Fos protein has a protein partner jun that is already present in the cytoplasm (jun is already phosphorylated once). Jun binds to fos to form a fos-jun heterodimer.  MAP kinase then phosphorylates the fos-jun heterodimer (once on each molecule).  The phosphorylated heterodimer is also known as AP1. AP1 is a transcription factor that re- enters the nucleus and binds to the promoter of the c-myc gene, which it then transcribes.  The c-myc mRNA leaves the nucleus and is translated into c-myc protein in the cytoplasm. The c-myc protein also has a protein partner, MAX, in the cytoplasm.  C-myc binds to MAX to form a heterodimer and is also phosphorylated by MAP kinase (once on each molecule).

o It is possible for myc to bind to myc or MAX to bind to MAX (homodimers) using the leucine zippers on the molecules o When there is only MAX present, MAX-MAX homodimers are formed and bind to DNA, blocking the transcription of E-box proteins because there is no transcriptional activation domain o When myc is present, the myc-MAX homodimer forms and binds to DNA, transcribing the E-box proteins because myc has a TAD.  This heterodimer is also a transcription factor that re-enters the nucleus and binds to the promoters of E box proteins. These proteins include: o elF4e -> promotes protein synthesis o ODC -> (ornithine decarboxylase) takes ornithine (from urea cycle) and produces polyamines (characteristic of S phase cytoplasm; involved in chromosomal condensation) o Cyclins o CDK phosphatase -> an enzyme that removes phosphase from CDK (cyclin dependent kinase) and activates them  CyclinD – CDK4 -> phosphorylates Rb protein (retinoblastoma), which is normally bound to E2F. E2F then falls off of Rb and is involved in DNA replication.  CyclinG – CDK2 -> phosphorylate histone kinases and p53 (turns on the p53 DNA damage checkpoint)  Also involved in turning on molecules needed for chromosome condensation and the phosphorylation of nuclear lamins to change the nuclear shape.

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