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Diverse Roles of JNK and MKK Pathways in the Brain.

Yamasaki T, Kawasaki H, Nishina H - J Signal Transduct (2012)

Bottom Line: The c-Jun NH(2)-terminal protein kinase (JNK) plays important roles in a broad range of physiological processes.Phenotypic differences between knockouts of MKK4 and MKK7 have also been observed, suggesting that the JNK signaling pathway in the brain has a complex nature and is intricately regulated.This paper summarizes the functional properties of the major JNK signaling components in the developing and adult brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

ABSTRACT
The c-Jun NH(2)-terminal protein kinase (JNK) plays important roles in a broad range of physiological processes. JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 4 and MKK7, which are activated by various MAPKKKs. Studies employing knockout mice have demonstrated that the JNK signaling pathway is involved in diverse phenomena in the brain, regulating brain development and maintenance as well as animal metabolism and behavior. Furthermore, examination of single or combined knockout mice of Jnk1, Jnk2, and Jnk3 has revealed both functional differences and redundancy among JNK1, JNK2, and JNK3. Phenotypic differences between knockouts of MKK4 and MKK7 have also been observed, suggesting that the JNK signaling pathway in the brain has a complex nature and is intricately regulated. This paper summarizes the functional properties of the major JNK signaling components in the developing and adult brain.

No MeSH data available.


MKK4 and MKK7 have different functions in the developing brain. MKK4 and MKK7 both activate JNKs, which phosphorylate MT-associated proteins such as MAP1B and DCX. Activated MAP1B and DCX regulate neuronal migration and axon elongation in the developing brain. However, JNK activated by MKK4 regulates radial migration but not axon elongation, whereas JNK activated by MKK7 controls both radial migration and axon elongation. These differences between MKK7 and MKK4 functions also appear at the molecular level. The phosphorylation of MAP1B requires that JNK be activated by both MKK4 and MKK7. However, the phosphorylation of DCX requires JNK activation only by MKK7 and not by MKK4.
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fig2: MKK4 and MKK7 have different functions in the developing brain. MKK4 and MKK7 both activate JNKs, which phosphorylate MT-associated proteins such as MAP1B and DCX. Activated MAP1B and DCX regulate neuronal migration and axon elongation in the developing brain. However, JNK activated by MKK4 regulates radial migration but not axon elongation, whereas JNK activated by MKK7 controls both radial migration and axon elongation. These differences between MKK7 and MKK4 functions also appear at the molecular level. The phosphorylation of MAP1B requires that JNK be activated by both MKK4 and MKK7. However, the phosphorylation of DCX requires JNK activation only by MKK7 and not by MKK4.

Mentions: Differences between MKK7 and MKK4 functions also appear at the molecular level. In Mkk4flox/flox Nestin-Cre brain, phosphorylation levels of MAP1B are reduced but DCX phosphorylation is not altered. In contrast, phosphorylation levels of both MAP1B and DCX are decreased in Mkk7flox/flox Nestin-Cre brain, suggesting that the MKK7-JNK and MKK4-JNK signaling modules in this organ are not identical. In line with this hypothesis, the scaffold protein JIP1 binds to JNK, MKK7, and DCX but not to MKK4. We therefore propose that differences in scaffold proteins and/or substrates involved in the MKK7-JNK versus MKK4-JNK pathways could cause the phenotypic divergence observed between Mkk7flox/flox Nestin-Cre and MKK4flox/flox Nestin-Cre mice (Figure 2).


Diverse Roles of JNK and MKK Pathways in the Brain.

Yamasaki T, Kawasaki H, Nishina H - J Signal Transduct (2012)

MKK4 and MKK7 have different functions in the developing brain. MKK4 and MKK7 both activate JNKs, which phosphorylate MT-associated proteins such as MAP1B and DCX. Activated MAP1B and DCX regulate neuronal migration and axon elongation in the developing brain. However, JNK activated by MKK4 regulates radial migration but not axon elongation, whereas JNK activated by MKK7 controls both radial migration and axon elongation. These differences between MKK7 and MKK4 functions also appear at the molecular level. The phosphorylation of MAP1B requires that JNK be activated by both MKK4 and MKK7. However, the phosphorylation of DCX requires JNK activation only by MKK7 and not by MKK4.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3307000&req=5

fig2: MKK4 and MKK7 have different functions in the developing brain. MKK4 and MKK7 both activate JNKs, which phosphorylate MT-associated proteins such as MAP1B and DCX. Activated MAP1B and DCX regulate neuronal migration and axon elongation in the developing brain. However, JNK activated by MKK4 regulates radial migration but not axon elongation, whereas JNK activated by MKK7 controls both radial migration and axon elongation. These differences between MKK7 and MKK4 functions also appear at the molecular level. The phosphorylation of MAP1B requires that JNK be activated by both MKK4 and MKK7. However, the phosphorylation of DCX requires JNK activation only by MKK7 and not by MKK4.
Mentions: Differences between MKK7 and MKK4 functions also appear at the molecular level. In Mkk4flox/flox Nestin-Cre brain, phosphorylation levels of MAP1B are reduced but DCX phosphorylation is not altered. In contrast, phosphorylation levels of both MAP1B and DCX are decreased in Mkk7flox/flox Nestin-Cre brain, suggesting that the MKK7-JNK and MKK4-JNK signaling modules in this organ are not identical. In line with this hypothesis, the scaffold protein JIP1 binds to JNK, MKK7, and DCX but not to MKK4. We therefore propose that differences in scaffold proteins and/or substrates involved in the MKK7-JNK versus MKK4-JNK pathways could cause the phenotypic divergence observed between Mkk7flox/flox Nestin-Cre and MKK4flox/flox Nestin-Cre mice (Figure 2).

Bottom Line: The c-Jun NH(2)-terminal protein kinase (JNK) plays important roles in a broad range of physiological processes.Phenotypic differences between knockouts of MKK4 and MKK7 have also been observed, suggesting that the JNK signaling pathway in the brain has a complex nature and is intricately regulated.This paper summarizes the functional properties of the major JNK signaling components in the developing and adult brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

ABSTRACT
The c-Jun NH(2)-terminal protein kinase (JNK) plays important roles in a broad range of physiological processes. JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 4 and MKK7, which are activated by various MAPKKKs. Studies employing knockout mice have demonstrated that the JNK signaling pathway is involved in diverse phenomena in the brain, regulating brain development and maintenance as well as animal metabolism and behavior. Furthermore, examination of single or combined knockout mice of Jnk1, Jnk2, and Jnk3 has revealed both functional differences and redundancy among JNK1, JNK2, and JNK3. Phenotypic differences between knockouts of MKK4 and MKK7 have also been observed, suggesting that the JNK signaling pathway in the brain has a complex nature and is intricately regulated. This paper summarizes the functional properties of the major JNK signaling components in the developing and adult brain.

No MeSH data available.