Tyrosine Kinases and Phosphatases: Enablers of the Porphyromonas gingivalis Lifestyle

Abstract

Tyrosine phosphorylation modifies the functionality of bacterial proteins and forms the basis of a versatile and tunable signal transduction system. The integrated action of tyrosine kinases and phosphatases controls bacterial processes important for metabolism and virulence. Porphyromonas gingivalis, a keystone pathogen in periodontal disease, possesses an extensive phosphotyrosine signaling network. The phosphorylation reaction is catalyzed by a bacterial tyrosine (BY) kinase, Ptk1, and a Ubiquitous bacterial Kinase UbK1. Dephosphorylation is mediated by a low-molecular-weight phosphatase, Ltp1 and a polymerase and histidinol phosphatase, Php1. Phosphotyrosine signaling controls exopolysaccharide production, gingipain activity, oxidative stress responses and synergistic community development with Streptococcus gordonii. Additionally, Ltp1 is secreted extracellularly and can be delivered inside gingival epithelial cells where it can override host cell signaling and readjust cellular physiology. The landscape of coordinated tyrosine kinase and phosphatase activity thus underlies the adaptive responses of P. gingivalis to both the polymicrobial environment of bacterial communities and the intracellular environment of gingival epithelial cells.

Keywords: Porphyromonas gingivalis; epithelial cells; polymicrobial; tyrosine kinase; tyrosine phosphatase.

Figure 1

Tyrosine kinases (Ptk1 and UbK1) and phosphatases (Ltp1 and Php1) in P. gingivalis. Both Ltp1 and Php1 can dephosphorylate and inactivate Ptk1. RprY and CdhR are transcriptional regulators controlled by UbK1 and Php1 respectively. The Php1/Ltp1-Ptk1 axis can control production of the FimA and Mfa1 fimbriae and extracellular polysaccharide (EPS). Processing and secretion of gingipain proteases requires specific patterns of tyrosine phosphorylation. Secreted Ltp1 can be inactivated by peroxide and pABA. Red dashed line indicates direct phosphorylation and blue dashed line indicates direct dephosphorylation.

Figure 2

Schematic of the impact of Ltp1 secreted within epithelial cells by P. gingivalis. Ltp1 dephosphorylates PTEN leading to proteasomal degradation. A reduction of PTEN levels relieves suppression of PI3K/Akt which upregulates RGCC and Zeb2. An increase in Zeb2 activity results in upregulation of IL-6 and vimentin. From Liu et al. [44].