Cell-matrix adhesion, cell migration, integrins, transglutaminases, atherogenesis, tumor metastasis

My research interests are in the field of cell-matrix interactions and adhesion-mediated signaling.  Cell-matrix interactions are important for regulation of cell growth, differentiation and migration and are often deranged in pathological conditions, including atherosclerosis and cancer.  Integrins comprise a major class of transmembrane receptors involved in cell-cell and cell-matrix adhesion and bidirectional signaling in various types of cells.  We found that the protein cross-linking enzyme transglutaminase (tTG or TG2) enhances cell-matrix adhesion and signaling via formation of stable ternary complexes with integrins and the ubiquitous extracellular matrix protein, fibronectin (Akimov et al., J. Cell Biol., 148:825-838, 2000, Figure 1). Our latest work shows that cell surface tTG promotes macrophage and cancer cell migration, stimulates the assembly of fibronectin matrices, and amplifies integrin signaling by fibroblastic cells (Zemskov et al., Front. Biosci., 11:1057-1076, 2006).   Ongoing efforts in the laboratory are focused on further characterizing the newly defined non-enzymatic role of this protein in cell adhesion and adhesion-mediated processes.  A novel project in the lab is aimed at understanding presently unknown cellular mechanisms of tTG externalization and regulation of its dynamics and enzymatic activity on the cell surface.  We also plan to examine a potential contribution of tTG to endothelial cell migration and angiogenesis. 

Our central hypothesis is that up-regulation of cell-matrix adhesion, migration and signaling by integrin-associated tTG contributes to vascular inflammatory and neoplastic diseases. Recent experiments in the laboratory demonstrated that tTG directly interacts with the receptor for platelet-derived growth factor (PDGFR) on the cell surface and amplifies joint signaling by integrins and PDGFR due to stimulation of the association between these two signal-transducing receptors.  Since abnormal activation of PDGFR signaling is a hallmark of many vascular proliferative disorders, we will explore the role of tTG in atherogenesis and restenosis in the vessel wall.

The newly defined adhesive function of this protein will be examined further in neoplastic cells.  Although previously recognized as tumor suppressor, tTG has recently been shown to increase locomotion and invasiveness of oncogene-transformed epithelial cells.  Since metastatic tumor cells often overexpress tTG, we will examine its role in cancer cell invasiveness and tumor metastasis.  The emerging function of this protein in tumor metastasis will be studied using a combination of biochemical, cell and molecular biological techniques and in vivo models of tumor formation.  Gaining further insights into the structure of the tTG-fibronectin receptor-ligand complex by NMR or X-ray crystallography should lead to rational design and generation of potent inhibitors of this interaction that might be useful for inhibition of cancer cell metastasis.