Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

Abstract

SUMMARY The c-Jun N-terminal kinases (JNKs) are members of a larger group of serine/threonine (Ser/Thr) protein kinases from the mitogen-activated protein kinase family. JNKs were originally identified as stress-activated protein kinases in the livers of cycloheximide-challenged rats. Their subsequent purification, cloning, and naming as JNKs have emphasized their ability to phosphorylate and activate the transcription factor c-Jun. Studies of c-Jun and related transcription factor substrates have provided clues about both the preferred substrate phosphorylation sequences and additional docking domains recognized by JNK. There are now more than 50 proteins shown to be substrates for JNK. These include a range of nuclear substrates, including transcription factors and nuclear hormone receptors, heterogeneous nuclear ribonucleoprotein K, and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Many nonnuclear substrates have also been characterized, and these are involved in protein degradation (e.g., the E3 ligase Itch), signal transduction (e.g., adaptor and scaffold proteins and protein kinases), apoptotic cell death (e.g., mitochondrial Bcl2 family members), and cell movement (e.g., paxillin, DCX, microtubule-associated proteins, the stathmin family member SCG10, and the intermediate filament protein keratin 8). The range of JNK actions in the cell is therefore likely to be complex. Further characterization of the substrates of JNK should provide clearer explanations of the intracellular actions of the JNKs and may allow new avenues for targeting the JNK pathways with therapeutic agents downstream of JNK itself.

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

“…Consistently, analysis of JNK activation by immunoblotting in six additional MM cases showed considerable increase of p-JNK in BM plasma cells (selected as CD138 + CD38 hi CD45 low/-) 32 in 5 out of 6 cases compared to normal B cells ( Figure 1B, left). Interestingly, we also observed that intensity of p-JNK2 (p-p54, which is the prominent spliced form of JNK2) was significantly higher than p-JNK1 (p-p46, the prominent spliced form of JNK1) 11 (Figure 1B,right), indicating that JNK2 activity was increased in myeloma plasma cells. Increased levels of p-JNK2 were also found in a panel of MM cell lines compared to p-JNK1 ( Figure 1C).…”

“…11 As these cellular responses are important in tumorigenesis, JNK signaling has been implicated in human cancers. 11,12 Two major JNK proteins, JNK1 and JNK2, are expressed ubiquitously and each has two different splicing isoforms (p46 and p54).…”

“…11 As these cellular responses are important in tumorigenesis, JNK signaling has been implicated in human cancers. 11,12 Two major JNK proteins, JNK1 and JNK2, are expressed ubiquitously and each has two different splicing isoforms (p46 and p54). 11 Although JNK1 and JNK2 have been considered redundant kinases, there is evidence for distinct or even opposing functions of JNK1 and JNK2 in tumorigenesis.…”

“…11,12 Two major JNK proteins, JNK1 and JNK2, are expressed ubiquitously and each has two different splicing isoforms (p46 and p54). 11 Although JNK1 and JNK2 have been considered redundant kinases, there is evidence for distinct or even opposing functions of JNK1 and JNK2 in tumorigenesis. [12][13][14][15] Thus, it has been reported that JNK2, but not JNK1, is essential for growth of various human cancer cells including lung, 16,17 glioblastoma, 18,19 prostate and skin.…”

Basal c-Jun NH2-terminal protein kinase activity is essential for survival and proliferation of T-cell acute lymphoblastic leukemia cells

“…JNK phosphorylates a broad spectrum of substrates distributed throughout different subcellular compartments (31). The balance among these site-specific components of JNK signaling determines the biological outcomes (31).…”