Abstract
JNK is a protein kinase, which induces transactivation of c-jun. The three isoforms of JNK, JNK1, JNK2, and JNK3, are encoded by three distinct genes. JNK1 and JNK2 are expressed ubiquitously throughout the body. By contrast, the expression of JNK3 is limited and observed mainly in the brain, heart, and testes. Concerning the biological properties of JNKs, the contribution of upstream regulators and scaffold proteins plays an important role in the activation of JNKs. Since JNK signaling has been described as a form of stress-response signaling, the contribution of JNK3 to pathophysiological events, such as stress response or cell death including apoptosis, has been well studied. However, JNK3 also regulates the physiological functions of neurons and non-neuronal cells, such as development, regeneration, and differentiation/reprogramming. In this review, we shed light on the physiological functions of JNK3. In addition, we summarize recent advances in the knowledge regarding interactions between JNK3 and cellular reprogramming.
Highlights
Mitogen-activated protein kinase (MAPK) signaling pathways regulate various cellular functions [1,2,3,4,5]
In mouse dorsal root ganglion (DRG) neurons, deletion of JNK3 slightly reduced neurite length, but deletion of either JNK1 or JNK2 led to a significantly greater reduction than that caused by the deletion of JNK3, suggesting that JNK3 may be a promising target for suppression of apoptosis with minimum adverse effects on neurite regeneration [81]
Mouse hindlimb ischemia (HLI) models lacking JNK3 showed significantly enhanced blood flow recovery in response to HLI compared with WT controls, suggesting that ischemia-induced JNK3 expression in the peripheral nerves played a role in the blood flow recovery process, by regulating pro-angiogenic genes [92]
Summary
Mitogen-activated protein kinase (MAPK) signaling pathways regulate various cellular functions [1,2,3,4,5]. MKK4 and MKK7 reportedly induce the activation of JNK via dual phosphorylation of Tyr and Thr residues [10,11]. The functional differences between splice variants remain unclear, but different tissues express distinct subsets of JNK isoforms, suggesting that JNK activation plays a crucial role in cellular function. It is well known that isoforms JNK1 and JNK2 play different roles in regulating c-Jun expression and cell proliferation [19,20]. The transcription-initiation site and the termination codon are located at exon 3 and exon 14, respectively [21] In mice, these isoforms are Jnk on chromosome 14. The objective of the current review was to summarize the role and intracellular signaling of JNK3 in the development, regeneration and differentiation/reprogramming in neuronal lineage cells and non-neuronal cells (e.g., astrocytes, pancreatic β-cells, cardiovascular cells)
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