Cells respond to stresses such as osmotic shock and heat shock by activating 
stress-activated protein kinases (SAPKs), including c-Jun N-terminal kinase 
(JNK) [1]. Activation of JNK requires phosphorylation of threonine and tyrosine 
residues in the TPY activation loop motif [2, 3] and can be reversed by the 
removal of either phosphate group. Numerous JNK phosphatases including 
dual-specificity phosphatases [4, 5], have been identified. Many stimuli 
activate JNK by increasing its rate of phosphorylation; however, JNK 
dephosphorylation is inhibited in cells after heat shock [6], suggesting that a 
JNK phosphatase(s) is inactivated. M3/6 is a dual-specificity phosphatase 
selective for JNK [7, 8]. We have previously expressed M3/6 in the mouse bone 
marrow cell line BAF3 in order to show that JNK activation by IL-3 is necessary 
for cell survival and proliferation [9]. Here we report that M3/6 dissociates 
from JNK and appears in an insoluble fraction after heat shock. These data 
identify M3/6 as a JNK phosphatase that is inactivated by heat shock and provide 
a molecular mechanism for the activation of JNK by heat shock.