Linked Life Data

19929856

Source:http://linkedlifedata.com/resource/pubmed/id/19929856

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2010-1-27
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1470-8728
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
426
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
91-8
pubmed:dateRevised
2010-3-8
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
A regulating role of the JAK2 FERM domain in hyperactivation of JAK2(V617F).
pubmed:affiliation
Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, U.S.A.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural