CNK1: A New Component in the Control of Insulin Signaling

Model for how insulin affects scaffold proteins called cytohesins and CNK1.

Model for how insulin affects scaffold proteins called cytohesins and CNK1.

The control of insulin release after a meal to mediate blood-glucose levels is an essential step in energy regulation. An external signal activates molecular pathways within the cell to control this process.

Junghwa Lim, Ph.D., a research fellow in the CCR Laboratory of Cell and Developmental Signaling ,working under Deborah Morrison, Ph.D., recently identified a new component of the insulin signaling pathway, called Connector Enhancer of KSR1, or CNK1. CNK1 is a scaffold protein, a pathway regulator that brings together several proteins allowing them to interact and transmit signals in the cell. A description of Dr. Lim and colleagues’ discovery was published in a recent issue of Genes & Development.

Since CNK1 is a scaffold protein, it contains several distinct regions capable of interacting with different types of proteins. To determine which specific proteins bind to CNK1, Dr. Lim and her fellow researchers isolated CNK1-containing protein complexes from cells grown in culture. Analysis of these complexes by mass spectrometery revealed that CNK1 binds to many different cellular proteins, but the most abundant interaction partners are from a class of proteins called cytohesins. Cytohesins participate in cellular signaling and function as specific activators of the enzymes ARF GTPases.

Since cytohesins have previously been shown to influence insulin signaling, Dr. Lim and her associates examined the effects of insulin on the interactions of CNK1 with other cellular components. They found that the association of CNK1 and the cytohesins was not affected when cell cultures were treated with insulin, but that addition of insulin changed the location of CNK1 in the cell, causing it to associate with the cell surface membrane.

Additional experiments revealed that inhibition of CNK1 production blocked the propagation of signals through the insulin pathway. Normally, when cells are stimulated by insulin, a protein called IRS1 is transported to the cellular membrane, where it interacts with other proteins and facilitates transmission of the insulin-initiated signaling pathway. However, in cells in which CNK1 has been depleted, there is a reduction in the movement of IRS1 to the membrane. A similar effect was observed for the cytohesins. When CNK1 was added back to the cells, signaling through IRS1 was restored.

Together, these results suggest that CNK1 makes a critical contribution to insulin signaling by facilitating the interactions of major players in this pathway. Specifically, it recruits cytohesins to the membrane, where they are able to activate the ARF GTPases. whose activity, in turn, is needed to recruit other proteins such as IRS1 to the membrane. The identification of the components and interactions that occur upon stimulation with insulin sheds light on how metabolic pathways may malfunction, and may lead to advances in treatment of diabetes and other diseases.

Summary Posted: 07/2010

Reference

Genes Dev. 2010 Jul 15;24(14):1496-506 PubMed Link