A Polarized Ca2+, Diacylglycerol and STIM1 Signalling System Regulates Directed Cell Migration

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2014 Jan 28

PMID 24463606

Citations 125

Authors

Feng-Chiao Tsai

Akiko Seki

Hee Won Yang

Arnold Hayer

Silvia Carrasco

Seth Malmersjo

Tobias Meyer

Affiliations

Soon will be listed here.

Abstract

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.

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References

Bisaillon J, Motiani R, Gonzalez-Cobos J, Potier M, Halligan K, Alzawahra W . Essential role for STIM1/Orai1-mediated calcium influx in PDGF-induced smooth muscle migration. Am J Physiol Cell Physiol. 2010; 298(5):C993-1005. PMC: 2867390. DOI: 10.1152/ajpcell.00325.2009. View

Chen T, Wardill T, Sun Y, Pulver S, Renninger S, Baohan A . Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature. 2013; 499(7458):295-300. PMC: 3777791. DOI: 10.1038/nature12354. View

Grynkiewicz G, Poenie M, Tsien R . A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985; 260(6):3440-50. View

de Chaffoy de Courcelles D, Roevens P, Van Belle H . R 59 022, a diacylglycerol kinase inhibitor. Its effect on diacylglycerol and thrombin-induced C kinase activation in the intact platelet. J Biol Chem. 1985; 260(29):15762-70. View

Vitorino P, Meyer T . Modular control of endothelial sheet migration. Genes Dev. 2008; 22(23):3268-81. PMC: 2600767. DOI: 10.1101/gad.1725808. View

Stauffer T, Ahn S, Meyer T . Receptor-induced transient reduction in plasma membrane PtdIns(4,5)P2 concentration monitored in living cells. Curr Biol. 1998; 8(6):343-6. DOI: 10.1016/s0960-9822(98)70135-6. View

Liou J, Fivaz M, Inoue T, Meyer T . Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc Natl Acad Sci U S A. 2007; 104(22):9301-6. PMC: 1890489. DOI: 10.1073/pnas.0702866104. View

Thastrup O, Cullen P, Drobak B, Hanley M, Dawson A . Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. Proc Natl Acad Sci U S A. 1990; 87(7):2466-70. PMC: 53710. DOI: 10.1073/pnas.87.7.2466. View

Franco S, Rodgers M, Perrin B, Han J, Bennin D, Critchley D . Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat Cell Biol. 2004; 6(10):977-83. DOI: 10.1038/ncb1175. View

10.

Yang S, Zhang J, Huang X . Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell. 2009; 15(2):124-34. DOI: 10.1016/j.ccr.2008.12.019. View

11.

Wei C, Wang X, Chen M, Ouyang K, Song L, Cheng H . Calcium flickers steer cell migration. Nature. 2009; 457(7231):901-5. PMC: 3505761. DOI: 10.1038/nature07577. View

12.

Honnappa S, Montenegro Gouveia S, Weisbrich A, Damberger F, Bhavesh N, Jawhari H . An EB1-binding motif acts as a microtubule tip localization signal. Cell. 2009; 138(2):366-76. DOI: 10.1016/j.cell.2009.04.065. View

13.

Kasturi R, Vasulka C, Johnson J . Ca2+, caldesmon, and myosin light chain kinase exchange with calmodulin. J Biol Chem. 1993; 268(11):7958-64. View

14.

Scott C, Dobson W, Botelho R, Coady-Osberg N, Chavrier P, Knecht D . Phosphatidylinositol-4,5-bisphosphate hydrolysis directs actin remodeling during phagocytosis. J Cell Biol. 2005; 169(1):139-49. PMC: 2171893. DOI: 10.1083/jcb.200412162. View

15.

Quann E, Merino E, Furuta T, Huse M . Localized diacylglycerol drives the polarization of the microtubule-organizing center in T cells. Nat Immunol. 2009; 10(6):627-35. DOI: 10.1038/ni.1734. View

16.

Chen Y, Chiu W, Chen Y, Lin P, Huang H, Chou C . Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis. Proc Natl Acad Sci U S A. 2011; 108(37):15225-30. PMC: 3174613. DOI: 10.1073/pnas.1103315108. View

17.

Zitt C, Strauss B, Schwarz E, Spaeth N, Rast G, Hatzelmann A . Potent inhibition of Ca2+ release-activated Ca2+ channels and T-lymphocyte activation by the pyrazole derivative BTP2. J Biol Chem. 2004; 279(13):12427-37. DOI: 10.1074/jbc.M309297200. View

18.

Clapham D . Calcium signaling. Cell. 2007; 131(6):1047-58. DOI: 10.1016/j.cell.2007.11.028. View

19.

Evans J, Falke J . Ca2+ influx is an essential component of the positive-feedback loop that maintains leading-edge structure and activity in macrophages. Proc Natl Acad Sci U S A. 2007; 104(41):16176-81. PMC: 2042181. DOI: 10.1073/pnas.0707719104. View

20.

Carrasco S, Merida I . Diacylglycerol, when simplicity becomes complex. Trends Biochem Sci. 2006; 32(1):27-36. DOI: 10.1016/j.tibs.2006.11.004. View