Activation of JAK2-V617F by Components of Heterodimeric Cytokine Receptors

Anuradha Pradhan,Que T Lambert,Lori N Griner,Gary W Reuther

doi:10.1074/jbc.m109.071191

Anuradha Pradhan, Que T Lambert + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m109.071191

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Abstract

The JAK2-V617F mutation is an important etiologic factor for the development of myeloproliferative neoplasms. The mechanism by which this mutated tyrosine kinase initiates deregulated signals in cells is not completely understood. It is believed that JAK2-V617F requires interactions with homodimeric cytokine receptors to elicit its transforming signal. In this study, we demonstrate that components of heterodimeric cytokine receptors can also activate JAK2-V617F. Expression of IL27Ra, a heterodimeric receptor component, enhanced the activation of JAK2-V617F and subsequent downstream signaling to activation of STAT5 and ERK. In addition, expression of components of the interleukin-3 receptor, IL3Ra and the common beta chain, activated JAK2-V617F as well as STAT5 and ERK. Importantly, expression of IL27Ra functionally replaced the requirement of a homodimeric cytokine receptor to promote the activation and transforming activity of JAK2-V617F in BaF3 cells. Tyrosine phosphorylation of IL27Ra was not required to induce activation of JAK2-V617F or STAT5, or to enhance the transforming activity of JAK2-V617F. Expression of IL3Ra or the common beta chain in BaF3 cells also enhanced the ability of JAK2-V617F to transform these hematopoietic cells. However, the heterodimeric receptor component IL12RB1 did not enhance the activation or transforming signals of JAK2-V617F in BaF3 cells. IL27Ra also activated the K539L and R683G JAK2 mutants. Together our data demonstrate that in addition to homodimeric receptors, some heterodimeric receptor components can support the activation and transforming signals of JAK2-V617F and other JAK2 mutants. Therefore, heterodimeric receptors may play unappreciated roles in JAK2 activation in the development of hematopoietic diseases including myeloproliferative neoplasms.

Highlights

Members of the Janus kinase (JAK) family of non-receptor tyrosine kinases are important signal transduction regulators downstream of various cell surface receptors [11,12,13,14]
JAK2-V617F demonstrates deregulated kinase activity and it is believed that the V617F mutation interferes with the ability of the pseudokinase domain to negatively regulate the activity of the kinase domain [10, 16, 19, 20]
This correlates with clinical studies that indicate in cells from polycythemia vera patients, recombination leads to uniparental disomy resulting in two alleles of the JAK2-V617F gene [8, 9]

Summary

Introduction

Members of the Janus kinase (JAK) family of non-receptor tyrosine kinases are important signal transduction regulators downstream of various cell surface receptors [11,12,13,14]. Expression of either of the two components of the interleukin-3 receptor, IL3Ra or the common ␤ subunit, enhanced JAK2-V617F kinase activity and the ability of JAK2-V617F to transform hematopoietic cells.

Results

Conclusion