Receptor-dependent protein activation – without a receptor

Essential for triggering cellular reactions to hormones and neurotransmitters, activation of G-proteins was believed to be exclusively caused by receptors linking the inside of a cell with its surroundings. Now Jürgen Knoblich and his group at the IMP provide strong evidence for G-Protein activation solely by an intracellular protein with no receptor involved – opening up possibilities for the optimisation of many therapeutics.

“G-Protein activation was predominantly seen as a “relay station” integrating extracellular signals via membrane spanning receptors with intracellular responses. The central role of G-proteins in the cellular responses to regulating substances of the body makes their activation a major target for numerous powerful pharmaceuticals in humans. However, we now believe that a cellular mechanism exists which can activate these key proteins without extracellular stimulation. This fundamental insight could help gaining better understanding of disease mechanisms and will aid the development of novel therapies ” comments Jürgen Knoblich.

Published in the current issue of Cell, the work by Knoblich describes a role for a small protein (Pins, Partner of Inscuteable) in the localised activation of G-proteins in asymmetrically dividing cells of the developing fruit fly (Drosophila) nervous system. Autonomous activation of G-proteins is shown to be part of a synchronised interaction of several proteins in differentiating nerve cells. The receptor-independent activation of G-proteins is believed to support cellular polarity not only in developing cells of the nervous system but also in cells of sensory organs. Such establishment and maintenance of polarity is essential for correct cell differentiation.

Previous work by Stephen Lanier and colleagues at the Medical University of South Carolina showed the existence of Pins in humans and proved that they can activate G-proteins under controlled standard conditions. Taken together with the real life data from the fruit fly reported here, it is believed that receptor-independent G-protein activation plays an important role in human cell development.

Original Publication

Matthias Schäfer, Mark Petronczki, Daniela Dorner, Michael Forte, and Jürgen Knoblich: Heterotrimeric G Proteins Direct Two Modes of Asymmetric Cell Division in the Drosophila Nervous System. Cell 107: 183-194, 19 October 2001.