Gradient sensing Sample Clauses

Gradient sensing. ‌ One such a model is the local excitation, global inhibition (LEGI) model [63]. This model is based on the reciprocal actions of PI3K and PTEN and can explain the cAR1 cAR1/ cAMP Gα2βγ Gα2GTP Gβγ Gβγ/ Figure 1.2: A model for cAR1 - G protein signaling during chemotaxis. The membrane is populated with cAR1, complexed cAR1-Gα2βγ and Gα2βγ; the latter is in equilibrium with a fraction in the cytosol. Upon cAMP binding by cAR1, Gβγ dissociates from cAR1- Gα2βγ. At the leading edge it binds F-actin, either at the membrane or in the cytosol, which immobilizes it. At the posterior, it simply enters the cytosol. Possibly, the immobilisation is part of an F-actin - G protein feedback loop. The function of this loop could be beneficial to the stabilisation of forming pseudopods either by F-actin functioning as a scaffold for Gβγ signaling or by inhibiting suggested "backness" signals [59]. Gα2 increases its affinity for the membrane and for cAR1 upon activation which at the same time makes is available for reactivation and allows it to better activate downstream, membrane localized signaling components. It is possible that activated Gα2 remains coupled to cAR1 in its GTP bound form. The cAR1-Gα2 complex and free cAR1 show a higher mobility at the anterior [17], this is a direct result of the fact that cortex - membrane interactions are less tight there [64]. The local attenuation of the cortex allows for faster pseudopod growth. Since the cortex is a major inhibitor of cAR1 diffusivity this leads to higher reaction rates relevant to chemotaxis at the leading edge. observed amplification found in PI(3,4,5)P3 signaling. In this model, upon binding of cAMP, cAR1 quickly activates downstream components (PI3K) but at the same time a slower inhibitory response is initiated (mediated by PTEN) which becomes stronger over time. This eventually results in a situation where the leading edge still overcomes inhibition while trailing edge activation diminishes. This model almost perfectly explains the polarized behavior seen in PH-domains but it lacks the ability for cells to polarize in the absence of a gradient. This is because maintenance of activation is directly dependent on cAR1 signaling however; the same molecules can be used to replicate this observation if positive feedback loops are incorporated [32]. The addition of such feedback would lead to the existence of PI(4,5)P2 and PI(3,4,5)P3 enriched patches on the membrane which are indeed observed [74].