Genetics 9

Question 0

What domain on tyrosine kinase is responsible for ligand binding?

Answer 0

Globular Extracellular domain: extremely variable.

Question 1

Receptor Protein Tyrosine Kinases

Answer 1

Example: insulin receptor, growth factors (VEGF and EGF).

-Exist as monomers with 3 protein domains

Question 2

What is the catalytic domain of RPTKs?

Answer 2

Tyrosine kinase domain. Responsible for cellular signaling through processes such as autophosphorylation and substate phosphorylation

Question 3

RPTK ligands are in the form of…

Answer 3

dimers. Helps the two monomeric protein units come together and dimerize.

Question 4

How is Tyrosine kinase phosphorylation different than serine/threonine kinase phosphorylation?

Answer 4

• No conformational change induced in the protein

- Created binding sites for proteins that are specific to phosphorylated tyrosine residues.

Question 5

All amino acid sequences that allow binding to recruited substrates need to have a ….

Answer 5

Phosphotyrosine residue.

Question 6

SH2 domains

Answer 6

• responsible for localizing substrates around tyrosine kinase domain of the receptor.
• Counteracts high Km of tyrosine kinase by increasing concentration of substrate around the catalytic domain.

Question 7

How are receptors for RAPTKs different from RPTKs?

Answer 7

• Receptors for RAPTKs do not have a tyrosine kinase domain attached to them. Instead, need to recruit RAPTKs in order to provide catalytic activity.
• Recruit RAPTKs using interaction domain in cytoplasmic portion of receptor

Question 8

Janus Kinases

Answer 8

• JAK
• Type of RAPTK that associates with signaling receptors on cell membrane to provide catalytic activity.
• Contain FERM domain: binds to receptor
• Kinase domain: phosphorylation activity
• SH2 domain

Question 9

What needs to happen before JAKs can provide tyrosine kinase activity?

Answer 9

They need to cross-phosphorylate each other.

• After that, they can phosphorylate the tyrosine residues on the cytoplasmic domain of the receptor itself.
• Then, protein substrates can be recruited to the phosphotyrosines, similar to RPTK signaling.

Question 10

What about JAKs allows for a wider range of signaling?

Answer 10

They can form homodimers (JAK1 +JAK1) or heterodimers (JAK1+ JAK2)

Question 11

Src

Answer 11

• Type of RAPTK
• functions similarly to Jak.
• Has SH2 domain, no evidence that it uses it to bind to receptor. May use interaction domain.
• Can affect many different functions inside the cell

Question 12

RPTK Activation

Answer 12

1) Ligand binding induces receptor dimerization.
2) Dimerization leads to tyrosine kinase domain activity
3) Dimerization leads to inter-molecular trans-autophosphorylation
4) Autophosphorylation on tyrosines outside of catalytic domain
5) Trans-auto-P= essentail for substrate phosphorylation
- Autophosphorylated tyrosine residues serve as highly selected binding sites for specific cytoplasmic molecules.

Question 13

JAK/STAT signaling is important because it allows….

Answer 13

Direct access to the nucleus through STAT dimerization.

Question 14

STAT

Answer 14

• Signal Transducers and Activators of Transcription
• Recruited proteins that attach to phosphotyrosine residues on receptor that were phosphorylated by JAK/Src.
• Contain SH2 domains.
• After STATs are phosphorylated by JAKs on receptor, they dissociated and form dimers that travel to nucleus, influencing transcription.

Question 15

SOCS

Answer 15

Suppressors of Cytokine Signaling

• Used as feedback mechanism to prevent continuous activation of RAPTKs.
• Contains SH2 domain: allows it to bind to phosphotyrosines on receptor, prevents further signaling.

Question 16

PTPs

Answer 16

Protein Tyrosine Phosphatases

• Used to halt tyrosine kinase signal transduction.
• Binds using SH2 domain.
• Function by either dephosphorylating the receptor itself, or dephosphorylating recruited substrates after being activated.