Abstract
The c-Jun NH2-terminal protein kinase (JNK) is a Janus-faced kinase, which, in the nervous system, plays important roles in a broad range of physiological and pathological processes. Three genes, encoding for 10 JNK isoforms, have been identified: jnk1, jnk2, and jnk3. In the developing spinal cord, JNK proteins control neuronal polarity, axon growth/pathfinding, and programmed cell death; in adulthood they can drive degeneration and regeneration, after pathological insults. Indeed, recent studies have highlighted a role for JNK in motor neuron (MN) diseases, such as amyotrophic lateral sclerosis and spinal muscular atrophy. In this review we discuss how JNK-dependent signaling regulates apparently contradictory functions in the spinal cord, in both the developmental and adult stages. In addition, we examine the evidence that the specific targeting of JNK signaling pathway may represent a promising therapeutic strategy for the treatment of MN diseases.
Highlights
C-Jun NH2-terminal kinase (JNK) is a member of the mitogen-activated protein kinases (MAPKs): it was discovered more than 20 years ago as the protein kinase family responsible for the transactivation of c-Jun by phosphorylating the N-terminal Ser-63 and Ser-73 residues [1,2]
Like the other MAPKs, the activation and increased activity of JNK requires its dual phosphorylation at Tyr and Thr residues, mediated by MAPKKs namely MKK4 and mitogen-activated protein kinase kinase 7 (MKK7), which consist of a group of protein kinases with different biochemical properties [3,4]: MKK7 acts as a specific activator of JNK, whereas MKK4 can activate p38 MAPK; both MKK4 and MKK7 are selectively regulated by extracellular stimuli and show distinct affinity for JNK [4,5]
MKK4 and MKK7 activation is in turn mediated by various MAPKKKs; the JNK signaling pathway is modulated by different scaffold proteins, as the JNK-interacting protein (JIP)1, JIP2, and JIP3 [6,7,8]
Summary
C-Jun NH2-terminal kinase (JNK) is a member of the mitogen-activated protein kinases (MAPKs): it was discovered more than 20 years ago as the protein kinase family responsible for the transactivation of c-Jun by phosphorylating the N-terminal Ser-63 and Ser-73 residues [1,2]. While on one side JNK family has been described as involved in injury responses and stress-induced apoptosis in neurodegenerative diseases and, more recently, in the pathophysiology of neuropsychiatric disorders [22,23,24], on the other JNKs are able to influence neuronal differentiation, by directly targeting chromatin modifiers for modulating histone phosphorylation and acetylation [25]. They are involved in the regulation of transcription of those genes related to brain morphogenesis, together with those for axonal growth and pathfinding [18].
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