Growth Factors

Front 1

Describe the pathway of a tyrosine kinase receptor.

Back 1

1. When a ligand binds to the receptor, it causes two receptors to dimerize.

2. The two receptors cross phosphorylate each other.

3. This activates Grb2, which binds to the SH2 domain of the TK domain.

4. Grb2 (no catalytic activity) binds to SOS on its other side.

5. SOS (a GEF) converts alpha-GDP to alpha-GTP on the G protein RAS.

6. Ras activates the kinases Raf and MEK. MEK activates another kinase, ERK. ERK activates transcription of various genes. This is called a MAPK Cascade.

7. Deactivation by GAPs, phosphodiesterases, and internalization/degradation of GF receptors.

Front 2

What are the three domains of the tyrosine kinase receptors?

Back 2

1. Ligand Binding Domain
2. Single TM Domain
3. Tyrosine Kinase Domain

Front 3

Describe the pathway of a cytokine receptor.

Back 3

1. Cytokine (usually an interferon) binds to the receptor.

2. receptors dimerize

3. JAK is activated & phosphorylates receptor intracellular domain

4. STATs bind to the phosphorylated domain

5. JAK phosphorylates STATs

6. More STATs bind to and dimerize with receptor bound STATs

7. STAT dimers go to nucleus and activate transcription of iNOS, creating NO which neutralizes the threat that activated the immune cells in the first place.

8. To inactivate the pathway, PIA's inhibit STAT dimer formation; STAT dimers also activate transcription of SOCS, which prevent binding of JAK to STATS. This is negative feedback.

Front 4

What are some structural similarities and differences between cytokine and tyrosine kinase receptors?

Back 4

Cytokine and tyrosine kinase receptors both have a extracellular ligand binding domain and a single TM domain. Their intracellular domain differs. Tyrosine Kinases have intrinsic kinase activity on the domain. In cytokine receptors, there is no intrinsic phosphorylating activity. JAK phosphorylates the domain instead.

Front 5

Myeloproliferative Disease

Back 5

an activating mutation in JAK results in increased RBC's and platelets, and increased fibrous CT replacing bone marrow.

Front 6

Achondroplasia

Back 6

FGF receptor is always on, resulting in overproduction of p21, a cell cycle inhibitor. Bone growth is overly inhibited.

Front 7

Explain the relationship between certain growth factors and tumors/cancers.

Back 7

Constant activated of Ras results in hyperactivity of MAPK cascades, which lead to cell proliferation.

Also, Raf kinase mutation in which a COOH replaces & resembles the PO4. Similar outcome, but kinase cannot be de-phosphorylated/deactivated.

High [ERB-B2] in breast cancer.

Front 8

T/F: mutations that uncouple proto-oncogenes from their regulatory mechanism tend to lead to cancer.

Back 8

True; either by overexpression or gain of function

Front 9

T/F: only one copy of the proto-oncogene needs to be mutated in order to lead to cancer.

Back 9

True; this mutation is a dominant effect over the wild type