Enzymes implicated in unchecked cancer growth

23 December 2012

Small patches of fruit fly cells (coloured green) have lost Hippo pathway activity.

Image: Small patches of fruit fly cells (coloured green) have lost Hippo pathway activity. These will go on to form abnormal growths in the fly's wing.

Researchers have discovered an important link between a molecular pathway called Hippo, which is involved in regulating cell and tissue growth, and two enzymes that play a part in determining how our bodies use nutrients. The research indicates that these two enzymes may enable tumours to grow uncontrollably by escaping the usual regulation of the Hippo pathway.

Keeping cell growth under careful control is necessary to prevent the formation of tumours. Researchers studying fruit flies previously discovered that the Hippo pathway is an important player in this regulation - by repressing the abnormal tissue growth that occurs in many human tumours.

Nic Tapon and colleagues at Cancer Research UK's London Research Institute (now part of the Francis Crick Institute)  carried out the current work with partners in Moritz Rossner's lab at the Max Planck Institute of Experimental Medicine in Göttingen, Germany. They used a new technique called the Split-TEV system to screen thousands of genes to look for new Hippo pathway regulators.

Dr Tapon explained: "The Split-TEV system is a method to detect when two proteins stick to each other. Such interactions between proteins are at the heart of how cells function and talk to each other. By fusing two proteins of interest to two halves of an enzyme (in this case, an enzyme called Tobacco Etch Virus Protease) and monitoring the activity of the enzyme, we can determine whether the proteins are interacting.  The enzyme is only active when the two proteins are close enough to each other to bring the two halves of the enzyme together."

The work led to the discovery that enzymes called salt inducible kinases (SIK) appear to downregulate, or turn off, the Hippo pathway.

Dr Tapon continued: "The Hippo pathway is a major signalling pathway that prevents tumours in many organisms - from fruit flies to people. The new member of this signalling pathway we found, called SIK, has previously been implicated in sensing nutrient levels."

"This work shows that nutrition can potentially regulate cell tissue growth through Hippo signalling. Nutrients are the building blocks of all our cells but tumour cells have an altered ability to use them. This may give cancer cells a way to escape the Hippo pathway which, under normal circumstances, prevents tumours from growing."

The paper, Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila, was published in Nature Cell Biology.

  • London Research Institute scientists have discovered that enzymes called salt inducible kinases (known as SIK) appear to 'turn off' the normal cell growth regulation pathway that prevents tumours from forming.
  • The enzymes were previously shown to sense nutrients in our bodies - linking two important pathways and showing that nutrition can potentially play a part in regulating cell growth - and cancer.