Meena Jaggi Lab
The primary focus of my research is to identify and evaluate the functional significance of cell-cell adhesion molecules known as cadherins and catenins in cancer progression and to understand the regulation of cadherin/catenin complex activity by Protein Kinase D signaling. In-depth knowledge of molecular mechanisms involved in signal transduction of human cancers is critical for the development of biomarker for early detection of cancer and rationalized structure-based drug designing. We have identified a novel interaction between E-cadherin/ß-catenin complex and Protein Kinase D1 (PKD1), an important modulator of several kinase signal-transduction pathways in benign and malignant human diseases. Downstream signaling of the E-cadherin/ ß-catenin and PKD1 interaction alters malignant phenotype of cancer cells.
The cadherins are members of a large family of transmembrane glycoproteins that mediate calcium dependent homotypic adhesion and require association with the actin cytoskleton through cytoplasmic proteins called catenins. The cadherin family of proteins is implicated in cell sorting during normal development. Aberrant expressions of cadherins and catenins have been implicated in the carcinogenesis and invasiveness of tumor cells. Malignant transformation is often characterized by major changes in the organization of the cytoskeleton, decreased cell-cell adhesion, and aberrant adhesion-mediated signaling. Disruption of normal cell-cell adhesion in transformed cells contributes to enhanced tumor cell migration and proliferation, which leads to invasion and metastasis. This disruption can be achieved by down-regulating the expression of cadherin or catenin family members or by activation of signaling pathways that prevent the assembly of junctions. We are attempting to understand how the activity the cadherin/catenin complex is regulated.
PKD1 is a serine/threonine-specific kinase that performs a variety of functions in cells and is target-dependent. PKD1 has been shown to play a major role in a multitude of cellular functions including apoptosis, immune response, DNA synthesis, cell proliferation and invasion, Golgi trafficking and intracellular signal transduction. I have identified a novel interaction between E-cadherin and PKD1 that results in E-cadherin phosphorylation. Downstream signaling of the interaction alters cellular aggregation and motility of cancer cells. I have also shown down-regulation of PKD1 and aberrant expression of E-cadherin, N-cadherin and ß-catenin in human prostate cancer progression in three publications. ß-catenin, a distinct member of the cadherin-catenin protein complex that plays a dual role in cell adhesion as well as in Wnt (Wingless type) signaling pathway associated with cell proliferation. In addition, we will also study the ß-catenin subcellular modulation by the PKD1 and regulation of membrane trafficking of ß-catenin by PKD1.
Contact Information for Jaggi Lab:
Meena Jaggi, PhD