Epidermal Growth Factor Receptor neddylation is regulated by a desmosomal-COP9 (Constitutive Photomorphogenesis 9) signalosome complex

摘要

The outer layer of skin – the epidermis – forms a critical barrier against a range of stresses from the environment. The epidermis itself consists of multiple layers of cells that are constantly being renewed. New cells are made in the deepest layer and move upwards until they eventually reach the skin’s surface. During this journey, the cells change the molecules they make in a process called epidermal differentiation. To maintain an effective barrier, the epidermis must balance the division of cells in the deepest layer with the differentiation of cells in the layers above. When activated, a protein called the Epidermal Growth Factor Receptor (or EGFR for short) encourages cells in the deepest layer to divide. However, it remains poorly understood how the balance between cells dividing and cells differentiating is achieved. The desmosome is a structure that can link together cells within the epidermis. Najor et al. now report a new interaction between the desmosome and a very large protein complex called the COP9- signalosome known to remove protein-based tags from other proteins. The experiments show that the COP9-signalosome results in the removal of these tags from EGFR. The status of the tags on EGFR regulates whether or not it is found at the cell surface. Najor et al. propose that that the desmosome acts as a scaffold and holds the COP9 signalosome close to EGFR. The enzyme in the COP9 signalosome then removes protein-based tags from EGFR, which triggers a series of events that remove EGFR from the cell surface. This dampens down the signals EGFR would normally send to make cells divide, and allows differentiation to proceed. The balance between cell division and differentiation is a fundamental process that is affected in many skin conditions, including psoriasis and atopic dermatitis. EGFR is also commonly overactive in cancers. As such, understanding how epidermal differentiation and cell division are controlled will shed light on a variety of disorders, allowing for the potential development of new treatments for these diseases.