Side 1 af 10
Answers for Exam - BMB508/BMB809,
June 6. 2012
Please note that the answers given are not the only way to answer correctly. It is possible to
provide correct answers, which are shorter and less comprehensive than the answers given
here. So please regard this as a guide to what should be included in the answers and not the
only correct way to answer.
, Side 2 af 10
Question 1. Inherited disease, cancer and G-proteins - (35%).
Costello syndrome is an inherited disease with many symptoms including overgrowth of the skin and
mental retardation. Costello syndrome is caused by mutations in the Ras gene of the Ras-MAPK
signaling pathway. The Ras-MAPK pathway can be activated by receptor tyrosine kinases (RTKs).
1. Give a brief description of RTKs and explain one main difference between RTKs and cytokine
receptors in the cytosolic part of the receptors.
Receptor tyrosine kinases (RTKs) are receptors located on the surface of the cell, which bind various
ligands, like growth factors. RTKs have an intrinsic tyrosine kinase in the cytosolic domain. In the
unbound state RTKs are monomers, with very low tyrosine kinase activity. When a ligand binds it
induces a conformational change which leads to formation of dimeric RTKs. In the dimeric RTKs the
tyrosine kinase on each monomer can phosphorylate an important tyrosine residue in the activation
lip of the other monomer (cross-phosphorylation). This causes the activation lip to move out of the
active site and allows binding of ATP or protein substrates. The activated kinases then phosphorylate
other tyrosine residues in the cytosolic domain and thereby allows docking/binding of signal
transducing proteins (like GRB2) with PTB or SH2 domains to the receptor. The dimeric RTKs typically
consist of two different monomers (For instance HER2/HER4).
In contrast cytokine receptor dimers are homodimers of the same monomer, also when they are
inactive. The cytokine receptors do not have an intrinsic kinase activity, but instead the cytosolic
domain of cytokine receptors associate with a JAK kinase. Ligand binding to the inactive
homodimeric receptor induces a conformational change which brings the associated JAK kinases
close to each other and allows cross phosphorylation and activation. Phosphorylation of tyrosines in
the cytosolic domain of the cytokine receptor allows STAT transcription factors and other signaling
molecules with SH2 or PTB domains to bind and be activated.
2. In figure A shown below the Ras-MAPK pathway is depicted. Describe the pathway and explain
what takes place at points 1-6 (black boxes).
FIGURE A.
Answers for Exam - BMB508/BMB809,
June 6. 2012
Please note that the answers given are not the only way to answer correctly. It is possible to
provide correct answers, which are shorter and less comprehensive than the answers given
here. So please regard this as a guide to what should be included in the answers and not the
only correct way to answer.
, Side 2 af 10
Question 1. Inherited disease, cancer and G-proteins - (35%).
Costello syndrome is an inherited disease with many symptoms including overgrowth of the skin and
mental retardation. Costello syndrome is caused by mutations in the Ras gene of the Ras-MAPK
signaling pathway. The Ras-MAPK pathway can be activated by receptor tyrosine kinases (RTKs).
1. Give a brief description of RTKs and explain one main difference between RTKs and cytokine
receptors in the cytosolic part of the receptors.
Receptor tyrosine kinases (RTKs) are receptors located on the surface of the cell, which bind various
ligands, like growth factors. RTKs have an intrinsic tyrosine kinase in the cytosolic domain. In the
unbound state RTKs are monomers, with very low tyrosine kinase activity. When a ligand binds it
induces a conformational change which leads to formation of dimeric RTKs. In the dimeric RTKs the
tyrosine kinase on each monomer can phosphorylate an important tyrosine residue in the activation
lip of the other monomer (cross-phosphorylation). This causes the activation lip to move out of the
active site and allows binding of ATP or protein substrates. The activated kinases then phosphorylate
other tyrosine residues in the cytosolic domain and thereby allows docking/binding of signal
transducing proteins (like GRB2) with PTB or SH2 domains to the receptor. The dimeric RTKs typically
consist of two different monomers (For instance HER2/HER4).
In contrast cytokine receptor dimers are homodimers of the same monomer, also when they are
inactive. The cytokine receptors do not have an intrinsic kinase activity, but instead the cytosolic
domain of cytokine receptors associate with a JAK kinase. Ligand binding to the inactive
homodimeric receptor induces a conformational change which brings the associated JAK kinases
close to each other and allows cross phosphorylation and activation. Phosphorylation of tyrosines in
the cytosolic domain of the cytokine receptor allows STAT transcription factors and other signaling
molecules with SH2 or PTB domains to bind and be activated.
2. In figure A shown below the Ras-MAPK pathway is depicted. Describe the pathway and explain
what takes place at points 1-6 (black boxes).
FIGURE A.
