A nuclear tyrosine phosphorylation circuit: c-Jun as an activator and substrate of c-Abl and JNK

Abstract

The nuclear function of the c-Abl tyrosine kinase is not well understood. In order to identify nuclear substrates of Abl, we constructed a constitutively active and nuclear form of the protein. We found that active nuclear Abl efficiently phosphorylate c-Jun, a transcription factor not previously known to be tyrosine phosphorylated. After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl. Surprisingly, elevated levels of c-Jun activated nuclear Abl, resulting in activation of the JNK serine/ threonine kinase. This phosphorylation circuit generates nuclear tyrosine phosphorylation and represents a reversal of previously known signalling models.

Abl interconnects oncogenic Met and p53 core pathways in cancer cells

“…pcDNA.Abl KinÀ and pcDNA.Abl PP have been previously described. 24,28 psuper-shAbl and psupershp53 plasmids were generated according to the siRNA sequence previously described. Luciferase constructs were generated using mdm2, p21 WAF1 or Noxa promoters.…”

“…We next evaluated in GTL-16 cells whether c-Abl was required for Met-triggered anchorage-independent growth, which is a hallmark of oncogenic transformation. c-Abl inhibition, either pharmacologically, through shRNA interference, or by using a kinase dead form (Abl KinÀ ), 24 severely affected Met-triggered anchorage-independent growth in a dose-dependent manner (Figures 1c-e), indicating that c-Abl is required to execute the oncogenic transformation in cancer cells dependent on oncogenic Met.…”

Tarp regulates earlyChlamydia-induced host cell survival through interactions with the human adaptor protein SHC1

“…ABL2 (ARG) was found to be the strongest interaction partner shared by both serovariants (D and L2). The ABL kinases can be activated through interaction of their SH2 domains with cellular substrates (Lewis and Schwartz, 1998;Barilá et al, 2000). ABL1 and ABL2 have been shown to be among the human kinases that phosphorylate Tarp (Elwell et al, 2008; two (VAV2 and PI3K) that had previously been identified.…”

Jun, the oncoprotein

“…Recently Jun has also been identi®ed as a substrate of the Abl tyrosine protein kinase. The interaction is part of an interesting regulatory circuit in which phosphorylation of Jun by Abl leads to an activation of JNK (Barila et al, 2000).…”