Activating Janus kinase pseudokinase domain mutations in myeloproliferative and other blood cancers

Abstract

The discovery of the highly prevalent activating JAK (Janus kinase) 2 V617F mutation in myeloproliferative neoplasms, and of other pseudokinase domain-activating mutations in JAK2, JAK1 and JAK3 in blood cancers, prompted great interest in understanding how pseudokinase domains regulate kinase domains in JAKs. Recent functional and mutagenesis studies identified residues required for the V617F mutation to induce activation. Several X-ray crystal structures of either kinase or pseudokinase domains including the V617F mutant of JAK2 pseudokinase domains are now available, and a picture has emerged whereby the V617F mutation induces a defined conformational change around helix C of JH (JAK homology) 2. Effects of mutations on JAK2 can be extrapolated to JAK1 and TYK2 (tyrosine kinase 2), whereas JAK3 appears to be different. More structural information of the full-length JAK coupled to cytokine receptors might be required in order to define the structural basis of JH1 activation by JH2 mutants and eventually obtain mutant-specific inhibitors.

Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident

“…The most common chromosomal abnormalities were cnLOH at 1p, 9p, 11q, and copy-number loss at 7q, 13q. These findings are consistent with published data indicating that the most frequent chromosomal abnormalities in MPNs are LOH at 1p, 9p, 14q, gain of chromosome 8,9,14, gain at 1q, and loss at 11q, 13q, 18p, 20q, while loss at 5q, 7p, 7q, and LOH at 17q have been observed in single cases. 41,42 The cnLOH we found at 1p in IR-unexposed PMF patients duplicated the pathogenic MPL W515R mutation in 2 out of 4 cases and also a novel MPL P222S variant in 1 case.…”

“…[4][5][6] The most frequent mutation of the JAK2 gene, JAK2 V617F, is associated with >95% of PV cases and with 50%-60% of ET and PMF cases. [5][6][7][8] The frequencies of the CALR gene mutations in patients with ET and PMF vary from 14% to 31% and from 12% to 35% of cases, respectively, as shown in meta-analysis of 19 studies. 9 A small proportion, 5%-10%, of MPN patients has activating mutations in the MPL gene.…”

Dawn of the dead: protein pseudokinases signal new adventures in cell biology

“…kinases [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], the latter field likely to mushroom with the development of new tools to study this most experimentally challenging of amino acid modifications [23,24]. The review articles that follow in this issue of Biochemical Society Transactions are contributions from key participants at the meeting, and contain a wealth of new information relevant to devotees of cell signalling.…”

“…The recent identification of catalytic activity among pseudokinase domains that are mutated in human disease, including the JAK family [16,17] and HER3/ErbB3 [7,11,27], raise the prospect of targeting these and other pseudokinases with specific small molecules in a manner akin to the clinically successful targeting of protein kinases. Intriguingly, as discussed in [7], it remains unclear how important any 'weak' catalytic activity of pseudokinases is with respect to in vivo functions, and naturally leads to the question of whether ATP-mimetic small molecules could modulate the cellular functions of these domains by modulating conformation.…”

Differential effect of inhibitory strategies of the V617 mutant of JAK2 on cytokine receptor signaling

“…JAKs (JAK1-JAK3 and TYK2) consist of 4 different domains (FERM, SH2-like, pseudokinase/JH2, and the kinase/JH1). 7 Comparison of the crystal structures of JAK2-JH2 wild-type (WT) and JAK2-JH2 V617F indicates that the aC changes conformation on valine to phenylalanine substitution and displays a more rigid configuration with an additional N-terminal turn, 8 likely because of an aromatic interaction between phenylalanine residues. In fact, F594 and F595 from aC and F617, are involved in a double T-shaped p-p stacking interaction, in which F595 plays a pivotal role in maintaining these interactions.…”