Structural Biochemistry/Lipid activation of protein kinases

Lipids regulate the amplitude, duration, and subcellular location of signaling by lipid second messenger responsive kinases. Generally, this activation is regulated by membrane targeting modules that regulate the function of kinase domains within the same polypeptide. Protein kinase C (PKC) acts as the primary lipid-regulated kinase, providing a prototype for lipid-controlled kinase activation that is followed by kinases throughout the kinome, such as Akt (Protein Kinase B).

Cellular membranes form a platform of intense signaling activity. Acting as the site where extracellular signals are first received by the cell, they not only recruit and activate effector molecules, but they also provide an initiation to the activated effector molecules throughout the cell. Protein kinases possess an extremely common class of effector molecules that transduce signals, coming from the plasma membrane. These kinases can be found in the plasma membrane, illustrated by the tyrosine kinase growth factor receptors, or can be either soluble or amphipathic membrane proteins that translocate on and off cellular membranes in response to appropriate signals. Soluble proteins are found by membranes through protein scaffolds, but there are amphipathic membrane kinases whose members directly bind lipid second messengers through specific membrane targeting modules.

For PKC, The interaction of the membrane-targeting modules on the membrane, with high affinity, produces a conformational change that releases an auto-inhibitory pseudosubstrate segment from the substrate-binding cavity, allowing substrate binding and downstream signaling. This active conformation depends on lipid binding. In the case of Akt, engaging the PH domain on membranes serves the purpose of allowing priming phosphorylations of Akt. Once phosphorylated at two key positions, Akt is locked in an active conformation, and, unlike PKC, activity is independent of lipid binding. On the other hand, activity is regulated by the phosphorylation state of Akt. Therefore, lipids control the activity of a phosphorylated PKC, an event that dissociates Akt activity from lipid binding.

Lipid second messengers relay an abundance of signals that control cell growth and survival. Direct binding of protein kinases to these lipid second messengers serves as a first step to transduce information into the cell. The activity of these kinases is regulated and deregulation of this activity results in pathological states such as cancer.