TY - JOUR
T1 - Preferential targeting of p39-activated Cdk5 to Rac1-induced lamellipodia
AU - Ito, Yuki
AU - Asada, Akiko
AU - Kobayashi, Hiroyuki
AU - Takano, Tetsuya
AU - Sharma, Govinda
AU - Saito, Taro
AU - Ohta, Yasutaka
AU - Amano, Mutsuki
AU - Kaibuchi, Kozo
AU - Hisanaga, Shin ichi
N1 - Funding Information:
We thank Dr. Toshiyuki Watanabe at Zeiss Japan for the use of the ELYRA confocal microscope. This work was supported in part by Grants-in-Aid for Scientific Research from MEXT of Japan ( 19057007 and 25290024 ) (S.H.).
PY - 2014/7
Y1 - 2014/7
N2 - Cdk5 is a member of the cyclin-dependent kinase (Cdk) family that plays a role in various neuronal activities including brain development, synaptic regulation, and neurodegeneration. Cdk5 requires the neuronal specific activators, p35 and p39 for subcellular compartmentalization. However, it is not known how active Cdk5 is recruited to F-actin cytoskeleton, which is a Cdk5 target. Here we found p35 and p39 localized to F-actin rich regions of the plasma membrane and investigated the underlying targeting mechanism in vitro by expressing them with Rho family GTPases in Neuro2A cells. Both p35 and p39 accumulated at the cell peripheral lamellipodia and perinuclear regions, where active Rac1 is localized. Interestingly, p35 and p39 displayed different localization patterns as p35 was found more at the perinuclear region and p39 was found more in peripheral lamellipodia. We then confirmed this distinct localization in primary hippocampal neurons. We also determined that the localization of p39 to lamellipodia requires myristoylation and Lys clusters within the N-terminal p10 region. Additionally, we found that p39-Cdk5, but not p35-Cdk5 suppressed lamellipodia formation by reducing Rac1 activity. These results suggest that p39-Cdk5 has a dominant role in Rac1-dependent lamellipodial activity.
AB - Cdk5 is a member of the cyclin-dependent kinase (Cdk) family that plays a role in various neuronal activities including brain development, synaptic regulation, and neurodegeneration. Cdk5 requires the neuronal specific activators, p35 and p39 for subcellular compartmentalization. However, it is not known how active Cdk5 is recruited to F-actin cytoskeleton, which is a Cdk5 target. Here we found p35 and p39 localized to F-actin rich regions of the plasma membrane and investigated the underlying targeting mechanism in vitro by expressing them with Rho family GTPases in Neuro2A cells. Both p35 and p39 accumulated at the cell peripheral lamellipodia and perinuclear regions, where active Rac1 is localized. Interestingly, p35 and p39 displayed different localization patterns as p35 was found more at the perinuclear region and p39 was found more in peripheral lamellipodia. We then confirmed this distinct localization in primary hippocampal neurons. We also determined that the localization of p39 to lamellipodia requires myristoylation and Lys clusters within the N-terminal p10 region. Additionally, we found that p39-Cdk5, but not p35-Cdk5 suppressed lamellipodia formation by reducing Rac1 activity. These results suggest that p39-Cdk5 has a dominant role in Rac1-dependent lamellipodial activity.
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U2 - 10.1016/j.mcn.2014.05.006
DO - 10.1016/j.mcn.2014.05.006
M3 - Article
C2 - 24877974
AN - SCOPUS:84902214798
SN - 1044-7431
VL - 61
SP - 34
EP - 45
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
ER -