a. Components of the kinase cascade of the RTK pathway can amplify the original

Question

a. Components of the kinase cascade of the RTK pathway can amplify the original signal (ligand+receptor).Start with the effect of activation of RAF and describe amplification of the signal for at least two downstream steps in the pathway to make your point. Please describe information you know from lecture and not the figure below!Rubric (4): Correctly explain activation of at least two steps downstream of MEK (2) and illustrate signal amplification using these steps (2).

b. Use the figure below and what you have learned this week to define “cross-talk”. Rubric (2): crosstalk defined using figure.

c. Again, use the figure below to specifically discuss why crosstalk will increase cell survival and cell proliferation in a cell with constitutively active Ga subunit!   To do this, identify GPCR components in the figure that you know, that are activated, and how they will inhibit apoptosis. Also, identify activated RTK components in the figure, that you know, and how they increase cell division. Rubric (4): GPCR components identified and linked to cell survival using the figure. RTK components ID’s and linked to cell proliferation using the figure.

Cytokines PKC PKA Ca2 Growth factors HB- GPCR RTK p120GAP She Ras RaGDS Tiam RASSF1 P45 PI45 134 RalA Ra B Ca2 RLIP cFos cJun Nuclous Cell survival Growth Differentiation Proliferation Motility Protein sorting Cellular architecture Actin rearrangement Apoptosis Cell-cycle arrest Microtubule network

Explanation / Answer

a) RAF is involves in an cascade called the MAPK cascade(?Mitogen-activated protein kinase) .

In the first step of this cascade , there is the activation of the RAS by the EGFR or FGFR.

Activated RAS then activates the protein kinase activity of the RAF kinase.

RAF kinase then activates MEK (MEK-1 and MEK-2) .

This activated MEK phosphorylates and activates the MAPK .

b. The three major MAPK cascades; extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and also include input from protein kinase B (AKT) signaling.

JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. The switch is modulated by the ERK, p38, and AKT pathways.

c. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs.

Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases.

Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signaling

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