Janus kinase 2–Heat shock protein 90 protein–protein interface (JAK2–HSP90 PPI)

The Janus kinase 2–Heat shock protein 90 (JAK2–HSP90) protein–protein interface is a vital regulatory complex where the chaperone HSP90 maintains the stability and functional conformation of the JAK2 tyrosine kinase (Marubayashi et al., 2010, J. Clin. Invest. [1]). JAK2 is a key mediator of signal transduction for various cytokine receptors, and its dysregulation is a hallmark of myeloproliferative neoplasms (MPNs) (Schoof et al., 2009, Blood [2]). The oncogenic V617F mutation in JAK2 increases its reliance on the HSP90 machinery, making the interface a high-priority therapeutic target (Fiskus et al., 2011, Clin. Cancer Res. [3]). Small molecule inhibitors targeting the ATP-binding pocket of HSP90, such as ganetespib, disrupt this interaction, leading to the polyubiquitination and proteasomal degradation of JAK2 (Bhalla et al., 2014, Blood [4]). This degradation effectively shuts down downstream STAT5 signaling and inhibits the proliferation of malignant cells (Waibel et al., 2011, Leukemia [5]). While potent, the clinical utility of targeting this interface is often limited by the systemic toxicities associated with broad HSP90 inhibition, such as ocular and gastrointestinal issues (Lannutti et al., 2011, Mol. Cancer Ther. [6]).

Other names

JAK2-HSP90 interactionJAK2-HSP90 complexJanus kinase 2-Heat shock protein 90 alpha/beta interfaceJAK2-HSP90 chaperone-client interaction

Disruption of the JAK2–HSP90 interaction, typically via HSP90 inhibition, prevents the chaperone-mediated stabilization of JAK2, leading to its ubiquitination and subsequent proteasomal degradation, thereby inhibiting downstream STAT signaling.