Janus kinase 2 activation mechanisms revealed by analysis of suppressing mutations.

ABSTRACT:

Background

Janus kinases (JAKs; JAK1 to JAK3 and tyrosine kinase 2) mediate cytokine signals in the regulation of hematopoiesis and immunity. JAK2 clinical mutations cause myeloproliferative neoplasms and leukemia, and the mutations strongly concentrate in the regulatory pseudokinase domain Janus kinase homology (JH) 2. Current clinical JAK inhibitors target the tyrosine kinase domain and lack mutation and pathway selectivity.

Objective

We sought to characterize mechanisms and differences for pathogenic and cytokine-induced JAK2 activation to enable design of novel selective JAK inhibitors.

Methods

We performed a systematic analysis of JAK2 activation requirements using structure-guided mutagenesis, cell-signaling assays, microscopy, and biochemical analysis.

Resul

SUBMITTER: Hammaren HM 

PROVIDER: S-EPMC6363912 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature