Positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger NHE1 for polarity of migrating cells.
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 fibroblasts 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 phosphotidylinositol 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.
Frantz
Christian
C
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
Karydis
Anastasios
A
Nalbant
Perihan
P
Hahn
Klaus M
KM
Barber
Diane L
DL
D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D002465:Cell Movement; D006224:Cricetinae; D005347:Fibroblasts / Q000378:metabolism; D006150:Guanine Nucleotides / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009154:Mutation; D017434:Protein Structure, Tertiary; D011522:Protons; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013347:Subcellular Fractions; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D027682:Cation Transport Proteins; D006150:Guanine Nucleotides; D011522:Protons; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D006160:Guanosine Triphosphate; D020764:cdc42 GTP-Binding Protein