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Accueil du site > Animations Scientifiques > Séminaires 2013 > Bertrand Fourcade - From integrin activation to reaction-diffusion models : How podosomes organizations can be described as local self-sustained excitation waves of localized PdtIns(4,5)2 synthesis.

Bertrand Fourcade - From integrin activation to reaction-diffusion models : How podosomes organizations can be described as local self-sustained excitation waves of localized PdtIns(4,5)2 synthesis.

Speaker : Bertrand Fourcade, LJC ENS de Lyon.

E-mail : bertrand.fourcade@ens-lyon.fr

When : thursday 24th october at 11 am

Where : Amphi C ENS de Lyon

Title : From integrin activation to reaction-diffusion models : How podosomes organizations can be described as local self-sustained excitation waves of localized PdtIns(4,5)2 synthesis.

Integrin receptors mediate interaction between cells and extracellular matrix. These receptors do not possess any catalytic properties by themselves and must recruit additional signaling molecules upon activation to transmit signal to the cell (outside-in signaling). Additionally, integrin activation is achieved by diffusing cytoplasmic partners such as talin and kindlins and leads to integrin conformational changes resulting in increased affinity towards extracellular ligands. This latter process generically termed inside-out signaling is essential for many cellular functions such as cell motility, mecano-transduction and matrix degradation. Our work focuses on the last steps of integrin activation. These steps take place on the membrane and in the vicinity of the integrin receptors thus enabling mathematical and computational modeling. Our purpose is to classify the geometrical shapes and the dynamic of adhesive meta-structures such as the invadosome rings in cells expressing SrcY527F, a constitutively active Src mutant. These structures can either form spots with a granulation of space or expending rings annihilating each other. Our analysis concentrates on a few fields representative of key biochemical and observable modules. First, we show how integrin activation leads to adhesion reinforcement through a positive feedback loop amplifying the activation of talin by PdtIns(4,5)2. This module is under the control of a field mimicking the local production of PdtIns(4,5)2 by the lipid kinase PIPKI-gamma. Second, we consider an inhibitory mechanism leading to irreversible disassembling of membrane bound adhesive complexes. The latter takes place on a comparable but not necessarily equal time scale to the former. Varying one of these two timescales in relation to the other leads to a rich catalogue of shapes that can be compared to experiments. Our computational model emphasizes the crucial role of local PdtIns(4,5)2 synthesis for adhesion reinforcement in the regime where this production is strong enough. We base our discussion in the framework of a diffusion-reaction model and we show that integrin activation can be discussed in the framework of self-sustained objects for out-equilibrium systems (auto-soliton). This model includes a key module corresponding to the two conformational states of integrin receptors and it is shown that this module introduces essential nonlinearities with localized excited states as solutions. Integrin diffusion is included in the model and it is shown that it favors the instability towards granulation. Starting from elementary biochemical rules which govern integrin activation, we show that the system possesses localized states of PdtIns(4,5)2 production (likely corresponding to activated integrins) which can be either static or dynamic in a wide range of parameters.

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