Concerted modulation of paxillin dynamics at focal adhesions by deleted in liver cancer‐1 and focal adhesion kinase during early cell spreading

Abstract

Deleted in Liver Cancer-1 (DLC1) is a RhoGTPase-activating protein (GAP) and a tumor suppressor often downregulated in cancers. It is localized to the focal adhesions (FAs) and its absence leads to enhanced cell migration, invasion, and metastasis. Although DLC1 interacts with focal adhesion kinase (FAK), talin, and tensin, its role in focal adhesions dynamics remains unclear. We examined the effect of DLC1 in Human Foreskin Fibroblasts and determined its localization, dynamics and impact on paxillin by Fluorescence Recovery After Photobleaching at both nascent and mature focal adhesions. During early cell spreading, DLC1 is preferentially localized at the inner/mature adhesions whereas phosphorylated paxillin occupies the outer/nascent FAs. In addition, DLC1 downregulates paxillin turnover in a process, that does not require its GAP activity. Instead, it requires the presence of FAK. Acting in concert, both DLC1 and FAK could provide a unique spatio-temporal mechanism to regulate paxillin function in tissue homeostasis.

Epidermal Growth Factor Activates the Rho GTPase-activating Protein (GAP) Deleted in Liver Cancer 1 via Focal Adhesion Kinase and Protein Phosphatase 2A

“…FAK expression and signaling is elevated in highly malignant cancers, which could be a result of not only activating a RhoGEF (41) but also inactivating a RhoGAP (in this case, DLC1). Because DLC1 and FAK work in concert to regulate paxillin dynamics in early cell spreading (22), this FAK-DLC1-PP2A network could provide an important spatiotemporal switch to regulate the dynamics of focal adhesions.…”

“…It has also been shown recently that DLC1-FAK interplay controls paxillin dynamics at focal adhesions during early cell spreading (22). While screening for potential mutational hotspots surrounding the focal adhesion-targeting and SRR of DLC1, two amino acid substitutions were identified, T301K and S308I, which reduced DLC1 RhoGAP activity (23).…”

Down-regulation of DLC1 in endothelial cells compromises the angiogenesis process

“…Since the focal adhesion molecule paxillin is known to negatively regulate angiogenesis [7] and DLC1 is suggested to modulate the protein level of paxillin [8], we examined the effects of DLC1 knockdown on paxillin protein levels. Immunoblotting results showed that the paxillin level was markedly increased in siDLC1 HUVECs (figure 2B).…”

DLC1: a tumor suppressor that regulates Rho signaling

“…Instead, it requires the presence of FAK. Both DLC1 and FAK are key regulators of focal adhesion assembly/disassembly that also regulate paxillin turnover at focal adhesions [4]. …”