Example of analysis of signaling network based on 3 small GTP - - PDF document

Example of analysis of signaling network based on 3 small GTP binding proteins: identification of oscillators

for rapid leukocytes adhesion triggering by chemokines = activation = inhibition

H-ras PI(3)K H-ras Raf1 Rac1 zPKC Rac1 PI(3)K PKB Rac1 Rac1 Pak RhoA zPKC zPKC Mek PLD zPKC RhoA PLD RhoA Raf1 Mek ERK PKB Raf1 Pak Raf1 Mek Raf1 Mek ERK PI(3)K PDK1 PDK1 PKB PKB Raf1

Level 1

2-molecules

zPKC PKB H-ras z PKC

RhoA Mek ERK PLD zPKC

+ _

Raf1

A

PI(3)K PDK1 H-ras Raf1 Mek PKB ERK

+ _

C

Level 2

pathway

Rac1 zPKC Pak

+ _

Raf1

B

RhoA Mek ERK PLD zPKC

+ _

Raf1

A

PI(3)K PDK1 H-ras Raf1 Mek PKB ERK

+ _

C

Pak Raf1

B

Rac1 zPKC

+ Level 3

network

_

A A A A A B B B B B c

switch on switch off by-stable (memory) negative feedback bifurcation

(non linearity-thresholding)

A B A B

+

= no signal

(futile circuit)

C B

+

A B c A

B

c

• scillator

A B c

+

A B A

B

c

memory oscillator = =

PI(3)K PDK1 H-ras Raf1 PKB PI(3)K H-ras Raf1

= Raf1 oscillator = H-ras bifurcation

PI(3)K H-ras Rac1 zPKC PKB PDK1 zPKC PKB Mek ERK Raf1

= PDK1 bifurcation + PKB oscillator = transient z PKC activation

Rac1 zPKC PKB Raf1

= rac1 bifurcation + rac1/PI(3)K by-stable circuit + PKB oscillator + rac1 oscillator

PI(3)K PDK1

H-ras PI(3)K PDK1 zPKC PKB Mek ERK Raf1

+

Rac1 zPKC PKB Raf1 PI(3)K PDK1 Rac1 zPKC PKB PI(3)K PDK1 Mek ERK Raf1 H-ras

rac1 bifurcation + PI(3)K bifurcation + H-ras bifurcations + PDK1 bifurcation + rac1 / PI(3)K by-stable circuit + rac1 oscillator + PKB oscillator + Raf1 oscillator

Rac1 zPKC PKB PI(3)K PDK1 Mek ERK Raf1 H-ras

Oscillatory output

(frequency, amplitude, duration)

Phenomenon

Examples of oscillatory behavior in biology Menstrual cycle Circadian rhythm Neutrophil chemotaxis NADPH-oxidase activation Protease release by PMNs during chemotaxis iCa2+movement

Agonist Phenomenon

n bifurcations + n by-stable circuits + n negative feedbacks + n oscillators, etc.

B C

Oscillation-dependent

A

Oscillation-independent

B C

Oscillation-dependent

A

Oscillation-independent

B C

Oscillation-dependent

A

Oscillation-independent

B C

Oscillation-dependent

A

Oscillation-independent (frequency, amplitude, duration)

specificity

Experimental data Computer modeling (signaling molecules are treated just as logic units) Identification of overall

• rganization of the system

(signaling networks are treated as logic circuits) Computer experiment Prediction of pharmacological effect