Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor
Class I cytokine receptors are key regulators of many processes within the body. The receptors use the JAK-STAT signalling pathway, the deregulation of which causes it to become an important pathway in oncogenesis. Despite this, the processes responsible for JAK2 activation by class I receptors remains elusive.
Previous studies using growth hormone and its receptor have led to a model of receptor activation where hormone induced receptor dimerization resulted in close proximity of the receptor intracellular domains and apposition of the activation loops within the catalytic domains of a pair of receptor-bound JAK2 kinases, leading to kinase activation. However, this model was superseded when it was demonstrated that the receptors exist largely as inactive dimers in the absence of a ligand.
This study showed the growth hormone receptor does indeed exist as a dimer, held together by transmembrane helices. The binding of the hormone converts these helices from their parallel basal state, to a left hand crossover, inducing the separation of the helices, the key outcome of which is the separation of the box1 sequences. This separation results in the removal of the pseudokinase domain, which is blocking the kinase domain on the other JAK2 in the pair and vice versa. This brings both kinase domain into productive apposition, activating JAK2.
The proposed mechanism is useful understanding the actions of growth hormone and may extend to other class I cytokine receptor family members. It also provides a molecular basis for understanding the oncogenic JAK2 mutations and therefore may be useful in the design of small-molecule inhibitors.