Autocrine loops with positive feedback enable context-dependent cell signaling.

摘要: We describe a mechanism for context-dependent cell signaling mediated by autocrine loops with positive feedback. demonstrate that the composition of extracellular medium can critically influence intracellular dynamics induced stimuli. Specifically, in epidermal growth factor receptor (EGFR) system, amplitude and duration mitogen-activated protein kinase (MAPK) activation are modulated positive-feedback loop formed EGFR, Ras-MAPK pathway, ligand-releasing protease. The response to transient input is short-lived when most released ligand lost cellular microenvironment diffusion and/or interaction an ligand-binding component. In contrast, prolonged or persistent efficient recapturing endogenous ligand. To study functional capabilities loops, we have developed mathematical model accounts release, transport, binding, signaling. find arises as result dynamic between parts loop. Using model, directly interpret experimental observations on responses cells ionizing radiation. human carcinoma cells, MAPK patterns short pulse radiation be sustained, depending type medium. On basis our propose this, potentially other, cytokine systems may serve modules