A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F)

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

JAK2 (Janus tyrosine kinase 2) is important for signalling through many cytokine receptors, and a gain-of-function JAK2 mutation in its pseudokinase domain, V617F, has been implicated in Philadelphia chromosome-negative myeloproliferative neoplasms. How this mutation hyperactivates JAK2 is poorly understood. In the present paper we report our findings that the V617F mutation has little effect on the Vmax of JAK2 kinase activity, but lowers the Km value for substrates. Therefore under physiological conditions where the concentration level of substrates is presumably below saturation, JAK2(V617F) exhibits hyperactivation compared with wild-type JAK2. This lower Km of JAK2(V617F) towards substrates requires the JAK2 FERM (4.1/ezrin/radixin/moesin) domain, as deletion of the FERM domain abolished this effect. We also show that, in contrast with its positive role in JAK2(V617F) hyperactivation, the FERM domain in wild-type JAK2 is inhibitory. Deletion or mutations of the FERM domain resulted in increased basal JAK2 kinase activity. The results of the present study provide the biochemical basis for how V617F hyperactivates JAK2, and identifies novel regulating roles of the JAK2 FERM domain to control kinase activity at different activation states.

Original languageEnglish (US)
Pages (from-to)91-98
Number of pages8
JournalBiochemical Journal
Volume426
Issue number1
DOIs
StatePublished - Feb 15 2010

Keywords

  • 4.1/ezrin/radixil/moesin (FERM) domain
  • Janus tyrosine kinase 2 (JAK2)
  • Kinase activity
  • Myeloproliferative neoplasm

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F)'. Together they form a unique fingerprint.

  • Cite this