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Understanding how cells form feet

A study published in the Journal of Cell Biology has revealed that a protein known as Arf1 plays a role in podosome formation by regulating the assembly of myosin-II within the cytoskeleton. The study was carried out by a team of researchers from King’s (Professor Gareth E Jones), the Mechanobiology Institute and National University of Singapore (led by Professor Alexander Bershadsky).

The cells in our immune system can only protect our bodies if they are able to track down potentially harmful bacteria or viruses. This means passing through or reaching deep inside the tissues and organs, to reach sites of infection. To assist cells moving through tissue, these cells have evolved structures that can be considered ‘cellular feet’. Known as podosomes, these protrusions, of which there can be about a hundred per cell, make contact with a material that surrounds all cells (the extracellular matrix), and secrete proteins that degrade it. This action helps the moving cell to wade through tissue that is otherwise composed of impassable layers of matrix and tightly packed cells. In cancer cells, enlarged podosomes are often present (known as invadopodia) and these participate in the processes of cancer cell invasion and metastases.

Like our own limbs, podosomes are composed of systems that physically support and facilitate their assembly, growth and movement. At the core of these cellular limbs is the cytoskeleton – a network of protein-based cables or filaments that provide structural support to cells, and at the same time are dynamically modified to produce the forces needed for cell movement. The main protein making up these filaments is known as actin.

Despite the importance of podosomes in immunity, the cellular mechanisms that control podosome formation were not clear. To better understand these mechanisms, researchers employed super resolution microscopy to observe and describe the molecular steps that occur during podosome formation.

When podosome forming cells were viewed under super resolution microscopes, the podosomes could be seen as dots surrounded by a ring. These structures were found underneath the cell surface. The dot was found to correspond to a cytoskeleton core made of actin filaments. The ring around the actin core was made up of specialized proteins involved in the formation of cell-matrix contacts such as talin, paxillin and vinculin (Figure). Interestingly, viewing the cells in this manner also revealed a protein called Arf1, which serves as a switch to activate or deactivate cellular processes in response to signals coming from outside the cell. Previously, this molecular switch was believed only to control the transport of material within cells. However, Arf1 could now be seen co-localised with podosome rings.

Following this line of investigation, the researchers went on to discover that removal of Arf1 from cells rendered them incapable of forming podosomes. In this case Arf1 was controlling proteins involved in the formation of the cytoskeleton. One protein found to be directly impacted by Arf1s presence in podosomes was myosin-II, a protein that confers contractility to the cytoskeleton. Importantly, myosin-II is not found in the cytoskeletal core of the podosome, however it is found at the periphery. When Arf1 was reduced, myosin-II increased, suggesting this molecular switch controls how much myosin is present in the area, as too much would prevent podosome formation.

As a result of this study, the team speculate that Arf1 regulates the formation of podosomes by repressing the activity of myosin-II in the cytoskeleton. The roles of Arf1 and myosin-II in podosome formation, which were previously unknown, provide valuable insights in our understanding of how cells, including those of the immune system, move through tissue. With larger podosome-like structures often found in cancer cells, such knowledge also sheds light on how and why some cells acquire the ability to spread around the body, invade tissues and form tumors. By targeting the Arf1 it is hoped that processes of cell migration, invasion and matrix degradation, which are all crucial steps in the onset of cancer, can be modulated.

Paper reference: Nisha et al (2016), Podosome assembly is controlled by the GTPase ARF1 and its nucleotide exchange factor ARNO, J Cell Biol Jan 2017, 216 (1) 181-197; DOI: 10.1083/jcb.201605104.