期刊
JOURNAL OF CELL BIOLOGY
卷 179, 期 3, 页码 403-410出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200704169
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- NCRR NIH HHS [C06 RR16490, C06 RR016490] Funding Source: Medline
- NIGMS NIH HHS [GM57464, R01 GM058642, GM58642, R01 GM057464, U54 GM064346, GM64343] Funding Source: Medline
A fundamental feature of cell polarity in response to spatial cues is asymmetric amplification of molecules generated by positive feedback signaling. We report a positive feedback loop between the guanosine triphosphatase Cdc42, a central determinant in eukaryotic cell polarity, and H+ efflux by Na-H+ exchanger 1 (NHE1), which is necessary at the front of migrating cells for polarity and directional motility. In response to migratory cues, Cdc42 is not activated in fibroblasts expressing a mutant NHE1 that lacks H+ efflux, and wild-type NHE1 is not activated in. broblasts expressing mutationally inactive Cdc42-N17. H+ efflux by NHE1 is not necessary for release of Cdc42-guanosine diphosphate (GDP) from Rho GDP dissociation inhibitor or for the membrane recruitment of Cdc42 but is required for GTP binding by Cdc42 catalyzed by a guanine nucleotide exchange factor (GEF). Data indicate that GEF binding to phosphoti-dylinositol 4,5-bisphosphate is pH dependent, suggesting a mechanism for how H+ efflux by NHE1 promotes Cdc42 activity to generate a positive feedback signal necessary for polarity in migrating cells.
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