L15: MAPK Pathway

Question 1

What order triggers effector proteins?

Answer 1

Signal, receptor, MAPKKK, MAPKK, MAPK then the effector protein

Question 2

What are the functions of ERK1/2?

Answer 2

Regulates proliferation, differentiation, survival, migration and development

Question 3

What do JNK 1-3 and p38 regulate?

Answer 3

They regulate apoptosis, differentiation, metabolism and inflammation

Question 4

How is the ERK1/2 pathway activated?

Answer 4

By different signals e.g. insulin, EGF and all go on to activate Grb2 and its SH3 domain binds to Sos
- causes Ras to release GDP and bind GTP, activating RAF which phopshorylaytes MEK 1/2 and then ERK 1/2

Question 5

What are ERK’s targets once activated?

Answer 5

ERK has nucleic and cytoplasmic targets

• in cytoplasmic it can activate PLA2 which regulates arachindonic (fatty) acid
• in nucleic causes activation of txn factor

Question 6

What can be used to dephosphorylate ERK?

Answer 6

PTP-SL and DUSPs

Question 7

What can abnormal ERK signalling be caused by?

Answer 7

Cancer, mutations in receptors, Ras, Mer or ERK2

Question 8

How is the p38 pathway activated?

Answer 8

By at least 2 MAPKK (3, 6 (or 4 but only in alpha form))

Question 9

What is the function of p38?

Answer 9

It activates MSK 1/2 (immune cells) & MSK 2/3 (gene expression)

Question 10

What forms of p38 are known to exist?

Answer 10

• alpha and beta: expressed in most tissue
• gamma: skeletal muscle
• delta: pancreas, intestine, adrenal gland, kidney and heart

Question 11

What causes activation of MAPK and how?

Answer 11

Phosphorylation of tyrosine and threonine at TGY

- induces conformational change in protein enabling ATP and substrate to bind

Question 12

What causes deactivation of MAPK?

Answer 12

By protein phosphotase 1 and 2A

Question 13

How does duration of phosphorylation affect cell fate?

Answer 13

Sustained: associated with apoptosis induction
Transient: growth factor induced survival

Question 14

What controls phosphorylation duration?

Answer 14

Phopsphotases

Question 15

How is p38 function regulated?

Answer 15

Via scaffold proteins which confer spatial and temporal regulation
- binds to multiple components of MAPK pathway and bring them into close proximity

Question 16

What is the role of KSRs (kinase supressor of Ras)?

Answer 16

• binds to C-RAF, MEK 1/2 and ERK 1/2
• interacts w G- protein beta gamma and heat shock proteins 70&90
• MEK is constitutively associated w KSR but only ERK binds in response to stimulus
• optimal expression levels of KSR required for maximal response of MAPK to signals

Question 17

What is the role of MEK partner 1 (MP-1)?

Answer 17

Promotes association of MEK w ERK and thus enhances ERK phosphorylation

• to increase MAPK signalling MP-1 requires its interacting protein p14, which localises MP-1 to endosomes
• MP-1 and p14 are essential for EGF dependent activation of ERK