Regulation of Myosin Function by Protein Kinases and Light Chains

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Cells crawl over surfaces, extend and retract surface protrusions, change shape, engulf other organisms, take up liquid nutrients and divide by splitting into two. These varied forms of cell movement are driven by myosin, a remarkable molecular motor that converts chemical energy into a force that is used to travel along, or pull on, actin filaments. Our research focuses on two ubiquitous classes of myosin: myosin-I and myosin-II. Myosin-I links cell membranes to actin filaments and is involved driving membrane shape changes. Myosin-II, also called muscle myosin, assembles into bipolar filaments that contract networks of actin filaments. We are investigating three mechanisms that regulate myosin-I and myosin-II activity. These regulatory processes are critical to ensure that movement or force generation occurs in the cell only where and when it is required. Our first research project involves a protein kinase, termed MHCK-A, that blocks the assembly of myosin-II into filaments. Interestingly, MHCK-A has a novel type of protein kinase domain and is the founding member of a family of atypical protein kinases termed the alpha-kinases. We have shown that the structure and catalytic properties of MHCK-A differ considerably from those of conventional protein kinase. We will further study the structure, catalytic and regulatory properties of MHCK-A in order to shed new light on this poorly understood but important kinase family. Our second project concerns two novel light chains, MlcB and MlcC, that we discovered as components of myosin-I. Myosin light chains, which stabilize and regulate the myosin motor domain, are normally 16 kDa in size, but MlcB and MlcC are only 8-kDa in size. We will examine how MlcB and MlcC bind to, stabilize and regulate myosin-I activity, and will also investigate the possibility that they bind to other proteins. Our third project involves a protein kinase, PakB, that activates myosin-I. We will pursue an intriguing observation that we have made which indicates that PakB plays a critical role in regulating the ability of myosin-I to link the plasma membrane to the underlying actin filament network. Our findings will advance the basic knowledge of how myosin-dependent cell motility is regulated. It will provide valuable information that can be employed to generate specific inhibitors to block motile processes, which could be useful for diseases such as cancer metastases or inflammation in which cell migration plays a central role. HQP will develop a diverse and comprehensive research skill set with expertise in molecular biology, structural biology, enzymology and cell biology.