Researchers make key discovery about cellular pathway linked to myriad of diseases

Researchers from the University of Dundee and the Francis Crick Institute have made a significant discovery about a cellular pathway associated with developmental defects and a myriad of diseases ranging from alopecia to colorectal cancer.

The research, jointly led by Dundee's Dr Gopal Sapkota and Professor Sir Jim Smith of the Crick, examined the role of a protein called PAWS1 in the Wnt signaling pathway, which is of fundamental importance in shaping developing embryos and controlling cell fate in adults.

Mutations that cause slight alterations in Wnt signaling can lead to the developmental defects and disease. The researchers have now demonstrated that PAWS1 plays a significant impact in controlling the Wnt signaling pathway.

"Abnormal Wnt signaling is associated with many cancers, particularly colorectal cancers," said Dr Sapkota. "Understanding how PAWS1 regulates Wnt signaling may therefore offer new opportunities and targets for potential interventions."

The Dundee-Crick team had previously made the discovery of PAWS1 as a protein associated with a range of signaling processes involved in the development of bone, cartilage and other tissues in the human body. In order to further understand its role in development and disease, they looked at frogs as the activation of Wnt signaling in frog embryos is known to cause a two-headed tadpole.

The researchers found that injection of PAWS1 into frog embryos resulted in two-head tadpoles, thus implicating PAWS1 in the control of Wnt signaling. When they removed PAWS1 from a human osteosarcoma cell line, they found that Wnt signaling was inhibited.

To further explore the molecular mechanisms through which PAWS1 controls Wnt signaling, the researchers discovered that PAWS1 interacts with Casein Kinase 1 alpha (CK1a), an enzyme that is known to regulate Wnt signaling.

They went on to map the determinants of PAWS1-CK1 interaction and subsequently demonstrated that PAWS1 mutations incapable of associating with CK1a not only fail to cause two-headed tadpoles but are also unable to activate Wnt signaling.

This leads to the prospect of scientists one day being able to use PAWS1 to correct potentially deleterious alterations to Wnt signaling and therefore prevent or treat the diseases associated with it.

Dr Sapkota continued, "Our uncovering of PAWS1 as a crucial regulator of CK1a in Wnt signaling represents a significant leap in our understanding of this important signaling pathway. CK1a has been known as an important player in Wnt signaling for two decades but its regulation had remained a mystery until now."

The findings are published in the current issue of EMBO Reports. Polyxeni Bozatzi, a PhD student in Dr Sapkota's lab, and Dr Kevin Dingwell, from Professor Smith's lab, are joint lead authors of this study.

Professor Smith said, "Although the precise function of PAWS1 was poorly understood, PAWS1 mutations are known to cause palmoplantar hyperkeratosis, a disease in which there is excessive skin cell growth on the soles and palms and can affect normal hair growth leading to conditions such as alopecia.

"Wnt signaling is known to play crucial roles in the maintenance of skin tissue and hair development. Our findings that PAWS1 is important player in Wnt signaling now offer an opportunity to establish whether the pathogenic PAWS1 mutations impact Wnt signaling to give rise to this disease."

"This research is an outcome of a long-standing collaboration between the Dundee and Crick labs. It represents a wonderful example of how collaboration facilitates key scientific discoveries."

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