Network Dynamics and Network Dynamics and Cell Physiology Cell Physiology John J. Tyson John J. Tyson Dept. Biological Sciences Dept. Biological Sciences Virginia Tech Virginia Tech
Collaborators Collaborators Budapest Univ. Techn Techn. & Econ. . & Econ. Budapest Univ. Bela Novak Novak Bela Attila Csikasz Csikasz- -Nagy Nagy Attila Andrea Ciliberto Ciliberto Andrea Virginia Tech Virginia Tech Kathy Chen Kathy Chen Jill Sible Sible Jill
A little history… A little history… - +CH 2 (COOH) 2 BrO 3 1970’s Fe 2+ BrCH(COOH) 2 Belousov-Zhabotinsky Fe 3+ Br - +CO 2 +… ½ C 6 H 12 O 6 NAD C 3 H 4 O 3 Yeast Glycolysis NADH C 3 H 6 O 3 Higgins, Prigogine … general principles of kinetics & thermo. Hess, Noyes … specific mechanisms of oscillations
l l i w s k r o w e t n g n i h c t i w s l a c i m e h f o c f y o g o s l s o a l n c h c e e h t t w , e r e n n n e a l m b i s s s i o h p t a n I r o f s e t a d i d n a c g n i s i m o r p e b s . m e s t y s n o i c t a e r l a c m i e h c
The Cell’s Computer… Hanahan & Weinberg (2000)
P Wee1 Cdc20 Cdc14 TFB A Wee1 P TFB I CycB APC-P APC Cdc14 Cdc20 Cdc25 P CycB Cdc14 Cdh1 Cdc25 CKI CycD CycB CycE TFI I Cdh1 CycA CycD TFI A CKI CKI CKI CycE CycA Cdc20 Cyc E,A,B CycE CycA TFE A CycD CycB CycA TFE I
“Machine-readable” form… d[C ycB ] ( ) ' ' = k + k [T FB ] − k + k [C dh1] [C ycB] − k [C K I][C ycB] 1 1 2 2 3 d t binding synthesis degradation − [W ee1][C ycB ] + [C dc25][C ycB ~P] k k 4 5 phosphorylation dephosphorylation ( ) ( ' ) k + k [C ycB] [C dc25] − [C dc25] d[C dc25] k [PPase][C dc25] 6 6 T 7 = − d t J + [C dc25] − [C dc25] J + [C dc25] 6 T 7 activation inactivation
� �� ��� � �� ��� � � � ������������ � � ���� � ���� ���� � ���� � ��� ���� ����� M-phase G1 ���� ����� G2 � �� ��� ��� ��� ��� ��� S-phase ����������
P Wee1 Cdc20 Cdc14 TFB A Wee1 P TFB I CycB APC-P APC Cdc14 Cdc20 Cdc25 P CycB Cdc14 Cdh1 Cdc25 CKI Network Motifs ! CycD CycB CycE TFI I Cdh1 CycA CycD TFI A CKI CKI CKI CycE CycA Cdc20 Cyc E,A,B CycE CycA TFE A CycD CycB CycA TFE I
Gene Expression linear rate of degradation 5 S rate (dR/dt) 0.5 response (R) S=3 S=2 R S=1 rate of synthesis 0 0 0 1 2 3 0 0.5 1 R signal (S) d k S R 1 = Signal-Response t = k S − k R , R ss 1 2 d k Curve 2
Protein Phosphorylation 2 Kinase 2 1 response (RP) ADP ATP 1.5 rate (dRP/dt) 1 R 1 RP 0.5 0.5 H 2 O P i 0.25 Phosphatase 0 0 0 0.5 1 0 1 2 3 RP Signal (Kinase) 1 R 0 “Buzzer” Goldbeter & Koshland, 1981
Protein Synthesis: Positive Feedback 0.6 S=16 S Open 0.5 S=8 response (R) 0.5 rate (dR/dt) S=0 0.4 R 0.3 0.2 EP E Closed 0.1 0 0 0 10 0 0.5 R signal (S) Bistability “Fuse” Griffith, 1968
Coupled Buzzers 1 1 response (R) S = R total S=0.5 S=1 S=1.5 E R SN RP 0.5 0.5 SN E EP 0 0 0 0.5 1 1.5 0 1 2 R signal (S) Bistability “Toggle”
1 e response (MPF) s a h p a t e m 0.5 interphase 0 0 1 2 signal (cyclin) Frog egg Wee1 S = Total Cyclin MPF MPF = MPF-P CycB (inactive) Cdc25 Cdc25-P
MPF activity depends on total cyclin concentration and on the history of the extract M Cyclin concentration increasing I � 14 MPF activity 12 10 8 6 � � � � � � 4 2 0 0 6 12 18 24 30 60 nM ∆ ∆ ∆ ∆ cyclin B Cyclin concentration decreasing inactivation threshold at 90 min � 14 MPF activity 12 10 8 � � 6 ��� � � � 4 2 0 0 6 12 18 24 30 60 nM ∆ ∆ cyclin B ∆ ∆ bistability Wei Sha & Jill Sible (2003)
1 Oscillations MPF 0.5 Hopf Hopf 0 0 1 2 cyclin response (MPF) cyclin cyclin 1 synthesis degradation APC sss uss sss MPF MPF-P (inactive) 0 0.0 0.5 signal (rate of cyclin synthesis) Cdc25 Cdc25-P
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If knock-out positive feedback loop, then oscillations become faster and smaller amplitude… With + feedback Without + feedback Figure 4. Pomerening, Kim and Ferrell
P Wee1 Cdc20 Cdc14 TFB A oscillator Wee1 P TFB I CycB APC-P APC Cdc14 Cdc20 Cdc25 P bistable switch CycB Cdc14 Cdh1 Cdc25 CKI CycD bistable switch CycB CycE TFI I Cdh1 CycA CycD TFI A CKI CKI CKI CycE CycA Cdc20 Cyc E,A,B CycE CycA bistable switch TFE A oscillator CycD CycB CycA TFE I
P Wee1 ������������ � Cdc20 Cdc14 TFB A � ���������� �� � � Wee1 P TFB I CycB APC-P ���������� APC �� �� Cdc14 ��� ���� Cdc20 Cdc25 P �� �� ��� ��� ��� ��� ��� CycB �������� Cdc14 Cdh1 �� �� � � � Cdc25 �������� � �� � CKI CycD CycB CycE �� �� TFI I ���������� Cdh1 �� �� CycA CycD TFI A CKI �� �� �� CKI CKI �� �� CycE CycA �� �� Cdc20 Cyc E,A,B ��� ��� ��� ��� �������� CycE CycA TFE A Fission Yeast CycD CycB CycA TFE I
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Nature, Vol, 256, No. 5518, pp. 547-551, August 14, 1975 Genetic control of cell size at cell division in yeast Paul Nurse Department of Zoology, West Mains Road, Edinburgh EH9 3JT, UK wild-type wee1 ∆ ∆ ∆ ∆
P Wee1 Cdc20 Cdc14 TFB A Wee1 P TFB I CycB APC-P APC Cdc14 Cdc20 Cdc25 P CycB Cdc14 Cdh1 Cdc25 CKI CycD CycB CycE TFI I Cdh1 CycA CycD TFI A CKI CKI CKI CycE CycA Cdc20 Cyc E,A,B CycE CycA TFE A CycD CycB CycA TFE I
#��� ∆ ∆ �����������$��!���� �����������$��!����% %&��'�!&����(���'�#����!�"� &��'�!&����(���'�#����!�"� #��� ∆ ∆ ∆ ∆ ∆ ∆ ��� #��� ∆ ∆ ∆ ∆ � ��� !��������,$&-%� ��������� ������'���&��/ ��""�$��%� �%�0&��% ��� ���� � �� � � � � � � ������������
P Wee1 Cdc20 Cdc14 TFB A Wee1 P TFB I CycB APC-P APC Cdc14 Cdc20 Cdc25 P CycB Cdc14 Cdh1 Cdc25 CKI CycD CycB CycE TFI I Cdh1 CycA CycD TFI A CKI CKI CKI CycE CycA Cdc20 Cyc E,A,B CycE CycA TFE A CycD CycB CycA TFE I
)&���!��!�������������!���*���������������!�!��������� )&���!��!�������������!���*���������������!�!��������� ��� ��� ∆ ∆ ∆ ∆ � ��� ��������� ��� ���� �� � � � � � � � ������������
P Wee1 Cdc20 Cdc14 TFB A Wee1 P TFB I CycB APC-P APC Cdc14 Cdc20 Cdc25 P CycB Cdc14 Cdh1 Cdc25 CKI CycD CycB CycE TFI I Cdh1 CycA CycD TFI A CKI CKI CKI CycE CycA Cdc20 Cyc E,A,B CycE CycA TFE A CycD CycB CycA TFE I
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