New Signaling Pathway for mTor-Dependent Cell Growth Discovered

cell growth
Left: Protein kinase N (PKN) is active and inhibits PI3KC2β (stained green). Right: PKN is missing. This causes PI3KC2ß to change location in the cell and be active. | Alexander Wallroth, FMP

A team led by the researcher Volker Haucke (Leibniz Research Institute of Molecular Pharmacology and Free University Berlin) has now discovered how to regulate a particular lipid kinase that is crucial for the inactivation of mTor complex 1 and thus a new target for treatment of diabetes and cancer.

Activation of mTor complex 1 in the cell is central to many vital processes in the body, for example, cell growth and metabolism. However, if this pathway is overactive, diseases such as diabetic insulin resistance or cancer can result. A team led by the researcher Volker Haucke (Leibniz Research Institute of Molecular Pharmacology and Free University Berlin) has now discovered how to regulate a particular lipid kinase that is crucial for the inactivation of mTor complex 1 and thus a new target for treatment of diabetes and cancer. The results have just been published in the renowned journal Nature Cell Biology .

Signaling pathways in body cells are enormously complex: in order for a particular mechanism to be triggered, multiple “switches” must be “flipped” in a fixed order. However, finding these “switches” can be tricky because of the cellular signaling involved in numerous substances and complexes of matter whose roles are not always easy to identify. For a long time, it was unknown how mTor complex 1 could be deactivated in the cell. Researchers at FMP identified this “switch” as early as 2017: A particular lipid kinase (PI3KC2β) acts as a natural brake on the protein mTor and ensures that mTor complex 1 is switched off, for example if certain hormonal signals such as insulin do not occur ,

Alexander Wallroth from Volker Haucke’s group has now studied in more detail how this lipid kinase is regulated. “We manipulated lipid kinase in different ways and looked at the effects that it has on mTOR activity and cell growth,” says the biologist. The researchers found a mechanism for inactivating the lipid kinase PI3KC2ß. An important role is played by another kinase, the protein kinase N (PKN). It inhibits the lipid kinase PI3KC2ß and thus provides indirectly for the activation of mTOR. The protein kinase N is regulated by growth factors: growth factors stimulate at the cell membrane the mTor complex 2, the second protein complex in which mTor is present in the cell. This in turn activates the PKN, which in turn deactivates the lipid kinase.

“We have found two other components that could be attacked pharmacologically,” explains Alexander Wallroth. Namely, by inhibiting PKN, the lipid kinase PI3KC2β is activated and finally mTOR-dependent cell growth is suppressed. On the other hand, when the growth factor signaling pathway, mTor complex 2 and, finally, PKN is activated, the lipid kinase remains inactive and mTOR complex 1 can promote cell growth. Inhibitors that could inhibit PKN are already known. However, these are not very specific and also block many other vital processes in the cell, so they can not currently be used in living tissue.

“What is particularly interesting about our results is that we have found a cell biological signaling pathway that connects the mTor complexes 1 and 2 with each other. For example, if you turn off 2, it also affects 1, “says Alexander Wallroth. Thus, the researchers were able to show in the previous work that the lipid kinase PI3KC2ß acts directly on the mTor complex 1, when it is activated. If the PKN is activated by mTor complex 2 and thus the lipid kinase is deactivated, this also has an effect on the mTor complex 1. Less was known about the mTor complex 2 in relation to complex 1. The present results now show that mTOR complex 2 contributes the activity of the important complex 1.