Computational Methods for Systems and Synthetic Biology
François Fages
Inria Saclay – Ile de France
Lifeware project-team
http://lifeware.inria.fr/
How do Cells Sense their Environment ?
Extra cellular ligands:
hormones: insulin, adrenaline, steroids, EGF, neighbor cells: Delta membrane protein
nutriments
light, pressure, … Membrane receptors:
• Multiple transmembrane a-helices receptors can induce a change of conformation inside
e.g. 7-TMR G protein-coupled, TGFβ, Notch
• Single a- helix receptors cannot…
e.g. Tyrosine kinases TRK
How can a single a- helix receptor transmit the signal from outside to inside ?
Receptor Tyrosine Kinase RTK Activation by Complexation
One RTK receptor with its ligand is inactive
L::exterior + R::membrane <=> (L-R)::membrane.
but two RTK receptors with their ligands can bind together on the membrane to form an active receptor complex (L-R)::membrane + (L-R)::membrane <=> ((L-R)-(L-R))::membrane.
which phosphorylates RAS in the cytosol (kinase activity)
RAS::cytosol =[((L-R)-(L-R))::membrane]=> RAS~{p}::cytosol.
Cell Signaling from Membrane Receptors to Gene Activation
5 MAPK (mitogen activated kinase) signaling pathways in budding yeast (Saccharomyces Cerevisiae)
with 5 cell responses
MAPK Signaling Cascade Input/output
• Input:
RAS activated by the RTK receptor activates RAF (MAPKKK kinase) RAS-GTP + RAF-P14-3-3 =>
RAS-GDP + RAF + P14-3-3
• Output:
phosphorylated MAPK moves to the nucleus and
phosphorylates a transcription factor which activates some gene expression RAF + … => …
… => MAPK~{T183,Y185}
MAPK Signaling Cascade Structure
Three levels of double phosphorylations
Cooperative Hill Type of Order 4-5
Stimulus/Response Curve
Cell-to-Cell Signaling
Xenopus embryonic skin [Gosh Tomlin 01] Pepper-salt effect in a grid of cells
Transmembrane proteins Delta (ligand) and Notch (receptor) are degraded.
Notch production is triggered by high Delta levels in neigboring cells
(if [D::c21]+[D::c23]+[D::c12]+[D::c32]<0.2 then 0 else ka,MA(kd)) for _<=>N::c22.
Delta production is triggered by low Notch concentration in the same cell
(if [N::c22] > 0.5 then 0 else ka,MA(kd)) for _ <=> D::c22.
At steady state, a cell has either the Delta or the Notch phenotype
Conclusion
• MAPK signaling cascade act as a switch by converting graded inputs into switch-like outputs.
• The stimulus/response curves become progressively steeper (ultrasensitive) as the cascade is descended.
• No response to small stimuli (noise filtering).
• Cell-to-cell signaling uses transmembrane proteins as ligands
• Cell-to-cell signaling can be modeled with reactions between neighbors over a grid of cell locations
