Signaling through ERBB receptors: multiple layers of diversity and control

The four known ERBB receptors in humans are involved in a broad range of cellular responses, and their deregulation is a significant aspect in a large number of disease states. However, their mechanism of action and modes of control are still poorly understood. This is largely due to the fact that the control of ERBB activity is a multilayered process with significant differences between the various ERBB members. In contrast to other receptor tyrosine kinases, the kinase domain of EGFR (ERBB1) does not require phosphorylation for activation. Consequently, the overall activation state of the receptor is controlled by constant balancing of activity favoring and activity suppressing actions within the receptor molecule. Influences of the membrane microenvironment and context dependent interactions with varying sets of signaling partners are superimposed on this system of intramolecular checks and balances. We will discuss current models of the control of ERBB signaling with an emphasis on the multilayered nature of activation control and aspects that give rise to diversity between ERBB receptors.