Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation

Abstract

Key Points Jak2 activation-loop–defective mutation results in partial interferon γ signaling, but Jak2 mutant mice die due to abolished EpoR signaling. Jak2 scaffold function mediates IFNGR complex integrity, activity, and physiological Jak1 localization.

Janus kinases and Src family kinases in the regulation of EGF-induced vimentin expression in MDA-MB-468 breast cancer cells

“…In summary, even though JAK Inhibitor I inhibits all JAK family members (with very similar IC 50 within nanomolar range) and inhibited EGF-induced vimentin protein expression in this study, the inability of siRNA-mediated silencing of individual JAK family members to phenocopy this effect is suggestive of compensatory mechanisms in this pathway. Similar compensatory effects among the JAK family members have been proposed by others in various cellular systems (Keil et al, 2014;Nakamura et al, 2008;Radtke et al, 2005). …”

“…Despite significant inhibition of EGF-induced vimentin protein, even at low concentrations of JAK Inhibitor I, we failed to detect any change in vimentin protein induction by EGF following silencing of individual JAK family members. Given that siRNA-mediated silencing of JAK1 resulted in an approximately three-fold increase in JAK3 mRNA, and previous reports of compensation between JAK family members in other models (Keil et al, 2014;Nakamura et al, 2008;Radtke et al, 2005), the inability of silencing of a specific JAK family member may be reflective of redundancy in this pathway. The compensatory increase in JAK3 with JAK1 silencing is particularly interesting, since unlike other JAK family members that display almost ubiquitous expression, expression of JAK3 is predominant in cells of hematopoietic lineage (Cornejo et al, 2009) and its low levels in MDA-MB-468 breast cancer cells may make it well placed to be induced and compensate for JAK1 silencing.…”

JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo

“…[12][13][14] This is to be expected given that chemical inhibition is less complete than gene deletion and evidence that JAK2 scaffolding functions, which would not be targeted by a JAK2 kinase inhibitor, might be important for its activity. 56 In conclusion, our work supports a role for JAK2 in primary CML SPC survival, and provides further preclinical evidence for studies combining TKI with RUX in CML patients. We also provide evidence of a role for JAK2 in activating STAT5-dependent survival signals in CML CD34…”

Inhibition of protein kinase II (CK2) prevents induced signal transducer and activator of transcription (STAT) 1/3 and constitutive STAT3 activation

“…Plasmids coding for the gp130 mutant ΔYY and stable transduced Ba/F3-gp130 cells thereof have been described previously [38]. Expression plasmids for murine Jak1 and Jak2 have been described previously [62]. Jak1 −/− MEFs have been described previously [47].…”