The gC1qR is a multifunctional cellular protein which interacts with components of complement, kinin, and coagulation cascades, and select microbial pathogens. It is a ubiquitously expressed, highly anionic cellular protein of 33kDA that was initially identified and characterized as a receptor for the globular heads of C1q, localized predominantly to the mitochondrial matrix but is also found in other cellular compartments, including the endoplasmic reticulum and nucleus, as well as the cell surface, where it may be associated with lipid rafts. Although the biologic significance of gC1qR’s multi-departmental distribution is yet to be elucidated, the relevance of gC1qR as an important modulator of ligands both inside and outside the cell is recognized increasingly.
Several binding partners have been identified for cell surface gC1qR, including C1q and high molecular weight kininogen. Interaction of these ligands with gC1qR leads to classical complement pathway activation with generation of inflammatory cytokines, cell adhesion, and activation of the kinin system with production of bradykinin and consequent vascular permeability, respectively. It has also been demonstrated that the C-terminal cytoplasmic tail of membrane type-1 metalloproteinase (MT1-MMP), a key enzyme primarily recruited to the leading edge of migrating tumor cells, binds gC1qR. Although a direct functional link between these two proteins remains to be established, this observation suggests that the transient association of gC1qR with MT1-MMP may be involved in mechanisms regulating the presentation of MT1-MMP at the surface of tumor cells. In this regard, enhanced gC1qR expression has been described in human cancers, particularly in adenocarcinomas.
In collaboration with Dr. Ellinor Peerschke of and Dr. Berhane Ghebrehiwet of Stony Brook, the role of gC1qR in different human tissues is the focus of our research effort. Most recently, we have compared gC1qR expression in normal, inflammatory, dysplastic and malignant tissues of both epithelial and mesenchymal origin employing immunohistochemical techniques. Malignancies of epithelial derivation demonstrated marked expression, suggesting a role for gC1qR as a potential new diagnostic and therapeutic target. Beyond that, our data demonstrate expression in normal/benign proliferating and continuously dividing cells, as well as in inflammatory lesions, suggesting a potential link between gC1qR expression and cell replication and activation.
Presently, we are working on the definitive localization of gC1qR in the cell employing EM and immunofluorescent techniques in order to better understand the role of gC1qR in different cellular processes, both normal and pathologic. In addition, we are working to define the mechanisms of up and down regulation of this protein which we believe to be part of the immunohistochemical signature of epithelial malignancies.
Biomarkers of Malignancy