Cdk5 regulation of calcium dynamics

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The general interest of our laboratory is to understand how protein kinases regulate specialized cell functions. We focus on cyclin-dependent kinases (Cdks) in general and Cdk5 in particular. Cdk5 is a serine/threonine kinase that has been strongly implicated in mammalian development, and thus, our long-term objective is to uncover the fundamental molecular and cellular mechanisms of Cdk5 regulation and function. Throughout our over two decades of Cdk5 studies, we have demonstrated that Cdk5 activity is regulated by specific protein activators and that Cdk5 interactions serve to enhance or inhibit diverse cellular functions. Our research breakthroughs define the basic roles and significance of Cdk5 in gene expression, cell differentiation and secretion among others. Our recent studies point to Cdk5 as a regulator of calcium (Ca2+) dynamics and cell proliferation. By taking advantage of the Cdk5-/- knockout and mouse embryonic fibroblast (MEF) model systems, we found that Cdk5-/- MEFs proliferate at a faster rate compared to wt. We further found greater ATP-induced IP3R-mediated Ca2+ release from the endoplasmic reticulum (ER) in Cdk5-/- MEFs. Since we found that Cdk5 interacts with IP3R, and IP3R type 1 has two potential Cdk5 phosphorylation sites, our premise is that Cdk5 controls IP3R1-mediated Ca2+ release from the ER, possibly through IP3R1 phosphorylation. Our data suggest that Cdk5 control of ER Ca2+ release limits Ca2+ influx into mitochondria. Because mitochondrial Ca2+ uptake is associated with transient mPTP opening and production of ROS, which promotes cell proliferation, our view is that Cdk5 controls ER-mitochondria Ca2+ crosstalk, regulating mitochondrial Ca2+ concentration ([Ca2+]m), transient mPTP opening and ROS level, and subsequently, cell proliferation. Indeed, Ca2+ is key to signal transduction pathways leading to different cellular activities, and it is possible that Cdk5-regulated Ca2+ dynamics accounts for Cdk5-regulated cell proliferation. Thus, in line with our general hypothesis that Cdk5 is key to an elaborate system of protein-protein interactions and phosphorylation events that modulate specific cellular processes, and our short-term goal of understanding the connections between Cdk5-controlled Ca2+dynamics and Cdk5-regulated cell proliferation, our specific aims are: (i) to examine Cdk5 regulation of the IP3R-mediated Ca2+ signaling pathway, and (ii) to investigate Cdk5 involvement in Ca2+-regulated, mitochondria-mediated functions. Our proposed research will (i) generate new and significant knowledge on Cdk5 and its fundamental role in controlling Ca2+ dynamics and cell proliferation, which will (ii) serve as foundation for our next steps in our program that aims to elucidate the importance of Cdk5 in mammalian development, and (iii) elevate the status of two HQP, who will dedicate 100% of their time on our research program, which will serve as their channels for training and development.