JNK Suppresses Apoptosis via Phosphorylation of the Proapoptotic Bcl-2 Family Protein BAD

Abstract

JNK has been suggested to be proapoptotic, antiapoptotic, or have no role in apoptosis depending on the cell type and stimulus used. The precise mechanism of JNK action, under conditions when it promotes cell survival, is not entirely clear. Here, we report that JNK is required for IL-3-mediated cell survival through phosphorylation and inactivation of the proapoptotic Bcl-2 family protein BAD. IL-3 withdrawal-induced apoptosis is promoted by inhibition of JNK but suppressed by expression of a constitutively active JNK. JNK phosphorylates BAD at threonine 201, thereby inhibiting BAD association with the antiapoptotic molecule BCL-X(L). IL-3 induces BAD phosphorylation at threonine 201, and replacement of threonine 201 by alanine generates a BAD mutant, which promotes IL-3 withdrawal-induced apoptosis. Thus, our results provide a molecular mechanism by which JNK contributes to cell survival.

Sustained JNK signaling by proteolytically processed HPK1 mediates IL-3 independent survival during monocytic differentiation

“…Activation of the JNK pathway is known to mediate IL-3 dependent survival of the hematopoietic progenitor cell line FDC-P1. 23 In addition, JNK activity has been reported to be necessary for myeloid differentiation. 24 Therefore, we first analyzed the kinase activity of endogenous JNK proteins in HPK1-N cells compared to stable FDC-P1 cell pools containing HPK1-C or empty vector (Figure 4a).…”

“…23 To test, if IL-3 treatment might also induce JNK activity in HPK1-N cells, we deprived the cells from IL-3 and tested phosphorylation of endogenous JNK proteins following readdition of IL-3. While JNK signaling was induced by IL-3 in FDC-P1 cells containing empty vector, HPK1-N cells displayed JNK activity already without IL-3 stimulation (Figure 4c, top panel).…”

The signalling axis mediating neuronal apoptosis in response to [Pt(O,O′-acac)(γ-acac)(DMS)]

“…The JNK1/2 pathway has been implicated in signalling events in many forms of neuronal apoptosis [36]. In response to a variety of extracellular stimuli, JNK1/2 phosphorylates and regulates the activity of members of the Bcl-2 family (Bcl-2, Bcl-xL, Bim and Bad) [37,38] and modulates Bcl-2 and Bax protein expression [37,39,40].…”

Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway

“…JNK also interacts with nontranscription factors, such as members of the Bcl-2 family, regulating apoptosis. Activated JNK can Role of JNK in radiation effects on neural stem cells T Kanzawa et al phosphorylate Bcl-2, BAD, and BH3-only proteins, such as Bim, Bmf and Dp5 (Yamamoto et al, 1999;Harris and Johnson, 2001;Lei and Davis, 2003;Yu et al, 2004). When Bcl-2 and these BH3-only proteins are phosphorylated, they cause Bax translocation to mitochondria, which releases cytochrome c from mitochondria, resulting in the induction of apoptosis.…”