期刊
JOURNAL OF CELL SCIENCE
卷 132, 期 5, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.224121
关键词
Cell signaling; Ras GTPase; Phosphatidylinositol lipid; Excitable system; Self-organization; Spontaneous migration
类别
资金
- AMED-CREST Japan Agency for Medical Research and Development grant [JP17gm0910001]
- Japan Society for the Promotion of Science (JSPS) [17J02075]
- Grants-in-Aid for Scientific Research [17J02075] Funding Source: KAKEN
Spontaneous cell movement is underpinned by an asymmetric distribution of signaling molecules including small G proteins and phosphoinositides on the cell membrane. However, the molecular network necessary for spontaneous symmetry breaking has not been fully elucidated. Here, we report that, in Dictyostelium discoideum, the spatiotemporal dynamics of GTP bound Ras (Ras-GTP) breaks the symmetry due its intrinsic excitability even in the absence of extracellular spatial cues and downstream signaling activities. A stochastic excitation of local and transient Ras activation induced phosphatidylinositol (3,4,5)-trisphosphate (PIP3) accumulation via direct interaction with Phosphoinositide 3-kinase (PI3K), causing tightly coupled traveling waves that propagated along the membrane. Comprehensive phase analysis of the waves of Ras-GTP and PIP3 metabolism-related molecules revealed the network structure of the excitable system including positive-feedback regulation of Ras-GTP by the downstream PIP3. A mathematical model reconstituted a series of the observed symmetry-breaking phenomena, illustrating the essential involvement of Ras excitability in the cellular decision-making process.
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