| Project/Area Number |
11680683
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Molecular biology
|
|---|
| Research Institution | Yokohama City University |
|---|
Principal Investigator |
HIRAI Syu-ichi School of Medicine, Dept Molecular & Cellular Biol. Yokohama City University, Assistant Professor, 医学部, 助教授 (80228759)
|
|---|
| Project Period (FY) |
1999 – 2001
|
| Project Status |
Completed (Fiscal Year 2001)
|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
|
|---|
| Keywords | MAP kinase / leucine zipper / MUK / MLK / JNK / MBIP / cerebral cortex / neurogenesis / MLK / Two-hybrid / シグナル伝達 |
|---|
| Research Abstract |
MAP kinase upstream kinase/dual leucine zipper-bearing kinase/leucine-zipper protein kinase (MUK/DLK/ZPK) is a MAPKKK class protein kinase that induces JNK/SAPK activation. We report here a protein named MBIP that binds to MUK/DLK/ZPK. MBIP contains two tandemly-orientated leucine-zipper-like motifs with a cluster of basic amino acids located between the two motifs. MBIP interacts with one of the two leucine-zipper-like motifs of MUK/DLK/ZPK and inhibits the activity of MUK/DLK/ZPK to induce JNK/SAPK activation. Notably, no similar effect was observed with another JNK/SAPK-inducing MAPKKK, COT/Tpl-2, showing the specificity of MBIP action. Furthermore, the over-expression of MBIP partially inhibits the activation of JNK by 0.3 M sorbitol in 293T cells. Taken together, these observations indicate that MBIP can function as a regulator of MUK/DLK/ZPK, a finding that may provide a clue to understanding the molecular mechanism of JNK/SAPK activation by hyperosmotic stress. To explore the significance of the MUK/DLK/ZPK-JNK signaling pathway in neural cell migration in vivo, we first examined the expression of MUK/DLK/ZPK protein and the distribution of active JNK in developing mouse brain at different embryonic stages and found a temporal induction of MUK/DLK/ZPK expression and JNK activation in immature neurons. Then we monitored the effect of the constitutive activation of the MUK/DLK/ZPK-JNK pathway on neural migration and differentiation in utero, and found an inhibitory effect of MUK/DLK/ZPK expression on the radial imigration of immature neurons. We also found that MUK/DLK/ZPK is located along microtubules as well as in Golgi apparatus in primary culture cells of E16 embryonic cortex, and that MUK/DLK/ZPK over-expression in COS-1 cells alters microtubule organization. These results strongly suggest that the MUK/DLK/ZPK-JNK pathway contributes to the regulation of neural cell migration at least in part via microtubules dependent cellular events.
|
