Research in our group is focused on understanding the molecular mechanisms of various cellular signaling pathways and their contribution to human diseases such as cancer. Currently the lab is centered on two major themes: the phosphatase biology and the ubiquitin biology.
Theme 1: Phosphatase biology
Phosphatases are a group of ubiquitously expressing enzymes, which are responsible for the removal of a phosphate group of various substrates in a cell. Phosphatases play a crucial role in nearly every cellular process, including metabolism, gene transcription and translation, cell-cycle progression, protein stability, signal transduction, and apoptosis. While several kinases (their counterpart enzymes) have been found to be intricately involved in human malignancies, studies on the role of phosphatases are very limited. Thus, in this theme we aim to systematically characterize the role of phosphatases and their associated complex network of proteins in cellular processes and human cancers by using cell and animal models through cell biology and proteomics approach.
With the generous funding support from Wellcome Trust/DBT India Alliance, we established a detailed interaction network of 143 human phosphatases, which contains about 85% novel interactions. Using this interaction proteomics approach, we readily established the concept of identifying novel functions for cellular phosphatases based on their associated partners. For example, we demonstrated that tumor suppressor phosphatase PTEN functions in endosome maturation via interacting with Rab7, a critical GTPase in this process. In another study, using similar approach, we revealed a fundamental role of PTEN in regulation of SNX27 retromer pathway, which governs glucose transport. Currently, we are focused on actively expanding the functional network of different families of phosphatases in the cell.
Theme 2: Ubiquitin biology
Ubiquitination is an ATP-dependent, highly ordered multistep enzymatic process, which results in the covalent attachment of ubiquitin to the substrate. Ubiquitin linked to the substrates serves as a molecular tag that marks proteins for either degradation by proteosome dependent pathway or destined to function in wide variety of functions in a proteosome independent manner. The human ubiquitin system comprises of hundreds of different enzymes including approximately 500 ubiquitin ligases, ~50 E2s, and nearly 100 deubiquitinating enzymes. Together, these factors target thousands of human proteins for degradation or mediate other cellular functions.
One of the key questions in the ubiquitin field is to identify various substrates for particular E3 and how different protein substrates are recognized by specific E3-ligase complex. Also, it is puzzling how different E3-ligases assemble into a specific complex in mediating a particular cellular function and how E3-complexes are assembled and disassembled during various cellular processes. In this theme, we seek to discover new components of the ubiquitin system and uncover basic knowledge about how their activities are regulated, what their substrates are, and how they contribute to diverse cellular functions.
Given the fact that several RING-finger E3s and HECT-domain E3s been classified as either tumor suppressors or oncogenes, along with the reported genetic alterations, abnormal expression or dysfunction of various ubiquitin components often accompanied by the occurrence of cancer and other human disorders, we foresee that a better understanding of the basic biology of the ubiquitination process will provide insight into human diseases.