Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells

The development and maintenance of tissues requires collective cell movement, during which neighbouring cells coordinate the polarity of their migration machineries. Here, we ask how polarity signals are transmitted from one cell to another across symmetrical cadherin junctions, during collective migration. We demonstrate that collectively migrating endothelial cells have polarized VE-cadherin-rich membrane protrusions, 'cadherin fingers', which leading cells extend from their rear and follower cells engulf at their front, thereby generating opposite membrane curvatures and asymmetric recruitment of curvature-sensing proteins. In follower cells, engulfment of cadherin fingers occurs along with the formation of a lamellipodia-like zone with low actomyosin contractility, and requires VE-cadherin/catenin complexes and Arp2/3-driven actin polymerization. Lateral accumulation of cadherin fingers in follower cells precedes turning, and increased actomyosin contractility can initiate cadherin finger extension as well as engulfment by a neighbouring cell, to promote follower behaviour. We propose that cadherin fingers serve as guidance cues that direct collective cell migration

A polarized Ca2+, diacylglycerol and STIM1 signalling system regulates directed cell migration

Ca2+ signals control cell migration by regulating forward movement and cell adhesion. However, it is not well understood how Ca2+-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 Ca2+ pulses, local depletion of Ca2+ in the endoplasmic reticulum and local activation of STIM1, supporting pulsatile front retraction and adhesion. At the same time, the mediator of store-operated Ca2+ influx, STIM1, is transported by microtubule plus ends to the front. Furthermore, higher Ca2+ pump rates in the front relative to the back of the plasma membrane enable effective local Ca2+ signalling by locally decreasing basal Ca2+ Finally, polarized phospholipase C signalling generates a diacylglycerol gradient towards the front that promotes persistent forward migration. Thus, cells employ an integrated Ca2+ control system with polarized Ca2+ signalling proteins and second messengers to synergistically promote directed cell migration

Ca2+ Signaling in Cytoskeletal Reorganization, Cell Migration, and Cancer Metastasis

Proper control of Ca2+ signaling is mandatory for effective cell migration, which is critical for embryonic development, wound healing, and cancer metastasis. However, how Ca2+ coordinates structural components and signaling molecules for proper cell motility had remained elusive. With the advance of fluorescent live-cell Ca2+ imaging in recent years, we gradually understand how Ca2+ is regulated spatially and temporally in migrating cells, driving polarization, protrusion, retraction, and adhesion at the right place and right time. Here we give an overview about how cells create local Ca2+ pulses near the leading edge, maintain cytosolic Ca2+ gradient from back to front, and restore Ca2+ depletion for persistent cell motility. Differential roles of Ca2+ in regulating various effectors and the interaction of roles of Ca2+ signaling with other pathways during migration are also discussed. Such information might suggest a new direction to control cancer metastasis by manipulating Ca2+ and its associating signaling molecules in a judicious manner