Cancer researchers found a new mechanism potentially explaining evolution of signalling pathways

Cancer researchers at the University of Helsinki, Finland, in trying to find a novel tumor suppressor gene, instead found an important evolutionary change that occurred in a key developmental signalling pathway. The finding suggests a potential mechanism for evolution of complex intercellular signalling pathways. The results are published in today’s issue of the journal Developmental Cell.

A relatively small number of evolutionary conserved genes are responsible for controlling the development of the diverse range of animal species. Most of these genes have been originally identified in fruit fly, based on the analysis of mutations that alter the body pattern of a developing embryo.

During embryonic development, cells regulate the growth and differentiation of each other by secreting extracellular signalling molecules (growth factors or morphogens), which bind to receptors present on the surface of other cells. The receptors in turn activate intracellular signalling pathway composed of proteins that relay the signal to the nucleus, activating specialized proteins called transcription factors. The transcription factors then affect expression of genes that induce cell growth and differentiation.

The signal transduction molecules and mechanisms of major developmental signalling pathways are thought to be evolutionary conserved between invertebrates and vertebrates in such a way that if a signalling pathway is present in a given organism, it includes all the major classes of components found in humans. Because of the lack of intermediate forms, the evolution of these complex signalling pathways is not understood in detail, and the emergence of signalling pathways with multiple specific and essential components has even been used as an argument against evolution.

Because multiple components of the Hedgehog (Hh) signalling pathway are defective in human cancers, Markku Varjosalo in Professor Jussi Taipale’s laboratory (the University of Helsinki and National Public Health Institute of Finland) cloned the gene for mammalian homolog of a key regulator of fruit fly Hh signalling pathway, Costal-2. However, further analysis of the function of the mammalian gene revealed that it did not function as a Hh pathway regulator, let alone as the tumor suppressor gene the researchers had hoped for. Instead, together with a group led by Prof. Rune Toftgård and Dr. Stephan Teglund from Karolinska Institutet, the researchers found that another gene (Suppressor of Fused), which has a minor role in Hh signalling in fruit fly is critical for Hh pathway regulation in mammals.

The finding is the first clear demonstration of a major difference in the function of conserved signalling pathways between species. The results also show that multi-component pathways evolve, in part, by the insertion of novel proteins between existing pathway components. This insertion mechanism can potentially explain a challenging aspect of evolutionary biology regarding the emergence of signalling pathways with multiple specific components.

Loss of Hh pathway activity can cause a variety of human birth defects, such as polydactyly, cyclopia and holoprosencephaly. On the other hand, inappropriate activation of the Hh signaling pathway can cause multiple types of human cancer, including the most common type of cancer in Caucasians (basal cell carcinoma) and the most common brain tumor in children (medulloblastoma). Therefore, the study of the Hh signalling pathway is important for the understanding of and developing cures for human disease.

The work was supported by the Academy of Finland, Biocentrum Helsinki, The University of Helsinki, the Sigrid Juselius Foundation, and Finnish Cancer Organizations.

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