Rho family GTPases bring a familiar ring to cell wound repair.

Repair of wounds to single cells involves dynamic membrane and cytoskeletal rearrangements necessary to seal the wound and repair the underlying cytoskeleton cortex. One group of proteins essential to the cortical remodeling is the Rho family of small GTPases. Recently we showed that the founding members of this GTPases family, Rho, Rac, and Cdc42, are all essential for normal single cell wound repair and accumulate at the wound periphery in distinct temporal/spatial patterns in the Drosophila cell wound model. In addition, these proteins communicate with one another and with the cytoskeleton to regulate their distribution in response to wounds. Unexpectedly, we found evidence for context specific Rho GTPase binding to downstream targets or "effectors" which cannot be explained solely by means of local GTPase activation. Here we discuss these observations in relation to similar studies in single cell wound repair in the Xenopus oocyte, and highlight how these cell wound models serve as powerful tools to understand both cell wound repair and Rho GTPase biology.

Rho family GTPase functions in Drosophila epithelial wound repair.

Epithelial repair in the Drosophila embryo is achieved through 2 dynamic cytoskeletal machineries: a contractile actomyosin cable and actin-based cellular protrusions. Rho family small GTPases (Rho, Rac, and Cdc42) are cytoskeletal regulators that control both of these wound repair mechanisms. Cdc42 is necessary for cellular protrusions and, when absent, wounds are slow to repair and never completely close. Rac proteins accumulate at specific regions in the wound leading edge cells and Rac-deficient embryos exhibit slower repair kinetics. Mutants for both Rho1 and its effector Rok impair the ability of wounds to close by disrupting the leading-edge actin cable. Our studies highlight the importance of these proteins in wound repair and identify a downstream effector of Rho1 signaling in this process.

The SH3 regulatory domain of the hematopoietic cell kinase Hck binds ELMO via its polyproline motif.

Eukaryotic EnguLfment and cell MOtility (ELMO) proteins form an evolutionary conserved family of regulators involved in small GTPase dependent actin remodeling processes that regulates the guanine exchange factor activity of some of the Downstream Of CrK (DOCK) family members. Gathered data strongly suggest that DOCK activation by ELMO and the subsequent signaling result from a subtle balance in the binding of partners to ELMO. Among its putative upward modulators, the Hematopoietic cell kinase (Hck), a member of the Src kinase superfamily, has been identified as a binding partner and a specific tyrosine kinase for ELMO1. Indeed, Hck is implicated in distinct molecular signaling pathways governing phagocytosis, cell adhesion, and migration of hematopoietic cells. Although ELMO1 has been shown to interact with the regulatory Src Homology 3 (SH3) domain of Hck, no direct evidence indicating the mode of interaction between Hck and ELMO1 have been provided in the literature. In the present study, we report convergent pieces of evidence that demonstrate the specific interaction between the SH3 domain of Hck and the polyproline motif of ELMO1. Our results also suggest that the tyrosine-phosphorylation state of ELMO1 tail might act as a putative modulator of Hck kinase activity towards ELMO1 that in turn participates in DOCK180 activation and further triggers subsequent signaling towards actin remodeling.