ERK and phosphoinositide 3-kinase temporally coordinate different modes of actin-based motility during embryonic wound healing

Abstract

SummaryEmbryonic wound healing provides a perfect example of efficient recovery of tissue integrity and homeostasis, which is vital for survival. Tissue movement in embryonic wound healing requires two functionally distinct actin structures: a contractile actomyosin cable and actin protrusions at the leading edge. Here, we report that the discrete formation and function of these two structures is achieved by the temporal segregation of two intracellular upstream signals and distinct downstream targets. The sequential activation of ERK and phosphoinositide 3-kinase (PI3K) signalling divides Xenopus embryonic wound healing into two phases. In the first phase, activated ERK suppresses PI3K activity, and is responsible for the activation of Rho and myosin-2, which drives actomyosin cable formation and constriction. The second phase is dominated by restored PI3K signalling, which enhances Rac and Cdc42 activity, leading to the formation of actin protrusions that drive migration and zippering. These findings reveal a new mechanism for coordinating different modes of actin-based motility in a complex tissue setting, namely embryonic wound healing.

TRP channels and STIM/ORAI proteins: sensors and effectors of cancer and stroma cell migration

“…Rac and Cdc42 activation, for example, is regulated by guanine‐nucleotide‐exchange factors which can be activated by PI3K‐mediated PIP 3 production and via an increase in the [Ca 2+ ] i (Benard et al ., ; Schmidt and Hall, ; Fukata et al ., ). PI3K activation could be linked to cytoskeletal reorganization, and ERK signalling regulates the actomyosin network by activation of Rho and myosin‐II (Li et al ., ). Several studies showed that different TRP channels elicit their effect on migration of stromal cells via these pathways.…”

The cellular and molecular mechanisms of tissue repair and regeneration as revealed by studies in Xenopus

“…Very little is known about the mechanisms that drive the propagation of Ca 2+ signaling across the epithelium, although a recent finding showed that Itpkb and its product InsP 4 , besides enhancing Rho activity and actin assembly, also facilitate Ca 2+ propagation across the epithelial tissue from the site of injury (Soto et al., ). Although it has been known from studies in other systems that both the actomyosin contraction and filopodial zippering are mechanical forces that help repair the wound (Wood et al., ), a recent study in Xenopus embryonic epithelium described a mechanism that temporally coordinates the function of these two distinct force‐generating machineries, thereby facilitating efficient embryonic wound healing (Li et al., ). This work showed that an early activation of Erk signaling initiates Rho activation and myosin‐2 phosphorylation, which in turn triggers actomyosin constriction for a quick phase of wound closure.…”

“…This work showed that an early activation of Erk signaling initiates Rho activation and myosin‐2 phosphorylation, which in turn triggers actomyosin constriction for a quick phase of wound closure. Later on, PI3K signaling takes over, activating Rac and Cdc42, and the mode of cell motility is transformed to filopodial zippering to seal the wound edges (Li et al., ). Intriguingly, coordinated actomyosin‐based contraction also participates in the rapid neuroepithelial wound healing in the developing Xenopus brain, which expels damaged neuroepithelial cells from the brain, thereby protecting the tissue from further cell death (Herrgen, Voss, & Akerman, ).…”

“…The large-sized and easy-to-culture Xenopus oocytes have been used to study singlecell wound healing, a fundamental process that shares many features in common with more complicated multicellular tissue and organ repair mechanisms (Sonnemann & Bement, 2011). Furthermore, the blastula stage embryo with thousands of cells (termed blastomeres) can be used to study multicellular scar-free wound healing (Davidson, Ezin, & Keller, 2002;Li, Zhang, Soto, Woolner, & Amaya, 2013;Soto et al, 2013). Finally, research on the tadpole and later stages can be explored to investigate more complex tissue repair mechanisms, such as tail, limb, and lens regeneration (reviewed in Beck et al, 2009).…”

Investigating the Cellular and Molecular Mechanisms of Wound Healing in Xenopus Oocytes and Embryos

“…Use pak1-gst mRNA to detect Rac1 and Cdc42 activities; to detect RhoA activity, coinject mRNA for egfp-rhotekinGBD and rhoa ). Details of a suggested selection of plasmidsincluding pCS2-GFP/mCherry-moesin, pCS107-RhoA, pCS107-Pak1-GST, and pCS107-rGBD-GST-can be found in Li et al (2013) and Soto et al (2013). All published plasmids have been deposited in the Amaya laboratory repository and are available on request.…”