Movement of cells is vital during processes such as wound healing and development. Where cells move is usually controlled by gradients of chemicals in the environment that guide them to particular destinations. These attractive chemicals, or chemoattractants, are detected by receptors on the cell surface, which signal to the cytoskeleton to control movement in the appropriate direction. This is known as chemotactic signalling, but how detection of a chemoattractant actually leads to movement is poorly understood. Researchers in Rob Kay’s group in the LMB’s Cell Biology Division have now identified a master regulator of chemotactic cell movement in the amoeba Dictyostelium.
Many signaling pathways inside cells involve modification of proteins by the addition of phosphate groups, termed phosphorylation. John Nichols and Peggy Paschke from Rob Kay’s group, in collaboration with the LMB’s Biological Mass Spectrometry and Proteomics facility, initially identified thousands of proteins that are phosphorylated in resting cells. When cells detected chemoattractants the phosphorylation state of many of these proteins changes, but, a group of around 80 stood out because they became phosphorylated in response to two different chemoattractants. This suggests that this group could be part of the core chemotactic regulatory mechanism.
Importantly, more than half of this core group of proteins were phosphorylated at the same short sequence of amino acids. Further investigation revealed that this core group were all phosphorylated by one particular protein, the atypical MAP kinase, ErkB. The researchers additionally observed that cells lacking ErkB move very poorly and have lost almost all sense of direction. Interestingly, targets of ErkB were identified as being regulators of movement rather than parts of the movement machinery itself, which positions ErkB as a master regulator in this system.
Dictyostelium cells chasing a micropipette that is releasing the
chemoattractant, cyclic-AMP. Robert Insall / Beatson Institute, Glasgow.
This work shows that much of the information controlling cell movement flows through a single master regulator, ErkB, and by identifying the targets of ErkB, defines many new proteins in the next layer of this complex control system. Study of chemotactic signaling in Dictyostelium has informed our understanding of the movement of many different types of cell, including cells of the human immune system, such as neutrophils. Understanding how this is controlled could lead to treatments that support the immune systems fight against many different diseases.
This work was funded by the MRC and the Karn Fund.
The Atypical MAP Kinase ErkB Transmits Distinct Chemotactic Signals through a Core Signaling Module. Nichols, JME., Paschke, P., Peak-Chew, S., Williams, TD., Tweedy, L., Skehel, M., Stephens, E., Chubb, JR., Kay, RR. Developmental Cell 48(4): 491-505.e9
Rob Kay’s group page