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Fig. 9. Working model of cell-cell contact loss and wound healing through integrin 5-PKC signal transduction to regulate cofilin dephosphorylation and peripheral actin reorganization. When actin filaments were affected presumably by extracellular cues or reagent-mediated morphological changes, integrin 5-mediated PKC Ser643 phosphorylation may cause the activation of focal adhesion molecules including FAK and SFK. The PI3K/Akt pathway may be linked to PKC through a transmodulatory loop (refer to text). Activation of focal adhesion molecules and PI3K/Akt correlates with the dephosphorylation of cofilin Ser3 upon OXO treatment, presumably via the activation of cofilin phosphatase, SSH1L (Nishita et al., 2004) and via SSH1L activation-mediated inhibition of LIMK1 activity (Soosairajah et al., 2005). In particular, OXO treatment can also cause localization of nonphosphorylated cofilin at cell peripheries. These can result in severing of peripheral actin filaments via the dephosphorylated and thus activated cofilin. This dynamic peripheral actin reorganization may lead to cell-cell contact loss, and thereby enhance wound healing. However, specific signaling linkage(s) to dynamically regulate PKC, FAK, SFK, and PI3K/Akt activity, and actin reorganization, is impaired in cells expressing integrin 5 lacking its whole cytoplasmic tail (right side) which appears to be crucial for association with and signaling to PKC, although signaling for Erk1/2-mediated cell proliferation, probably via intact transmembrane and extracellular domains is still possible. Therefore, integrin-PKC-mediated dynamic regulation of cofilin activity and peripheral actin reorganization is responsible for cell-cell contact loss in response to stimuli that cause morphological changes.

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