A polarized Ca2+, diacylglycerol and STIM1 signalling system regulates directed cell migration.
Ca(2+) signals control cell migration by regulating forward movement and cell adhesion. However, it is not well understood how Ca(2+)-regulatory proteins and second messengers are spatially organized in migrating cells. Here we show that receptor tyrosine kinase and phospholipase C signalling are restricted to the front of migrating endothelial leader cells, triggering local Ca(2+) pulses, local depletion of Ca(2+) in the endoplasmic reticulum and local activation of STIM1, supporting pulsatile front retraction and adhesion. At the same time, the mediator of store-operated Ca(2+) influx, STIM1, is transported by microtubule plus ends to the front. Furthermore, higher Ca(2+) pump rates in the front relative to the back of the plasma membrane enable effective local Ca(2+) signalling by locally decreasing basal Ca(2+). Finally, polarized phospholipase C signalling generates a diacylglycerol gradient towards the front that promotes persistent forward migration. Thus, cells employ an integrated Ca(2+) control system with polarized Ca(2+) signalling proteins and second messengers to synergistically promote directed cell migration.
1] Program of Cancer Biology, Stanford University School of MedicineStanford California 94305 USA [2] Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA [3] Institute of Molecular Medicine, National Taiwan University College of MedicineTaipei 100 Taiwan.
Feng-Chiao
FC
Tsai
Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA.
Akiko
A
Seki
Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA.
Hee Won
HW
Yang
Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA.
Arnold
A
Hayer
Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA.
Silvia
S
Carrasco
Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA.
Seth
S
Malmersjö
Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA.
Tobias
T
Meyer
D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1; D010738:Type C Phospholipases / Q000378:metabolism
D004075:Diglycerides; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D010738:Type C Phospholipases; D002118:Calcium