Identification of the 23 kDa subunit of tau protein kinase II as a putative activator of cdk5 in bovine brain

Ishiguro, Koichi; Kobayashi, Shunsuke; Onion, Akira; Takamatsu, Masako; Yonekura, S.; Anzai, Kentaro; Imahori, Kazutomo; Uchida, Tsuneko

doi:10.1016/0014-5793(94)80501-6

Cited by 146 publications

(95 citation statements)

References 37 publications

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“…Cdk5 and p35 cloned from bovine retina have the same cDNA sequences as those of bovine brain proteins (20). We note that recombinant p35 is expressed as a ϳ25-kDa protein, as described previously (22)(23)(24). The ϳ25-kDa protein (p25) is a truncated form of p35, but p25 has been shown to activate Cdk5.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation by Cyclin-dependent Protein Kinase 5 of the Regulatory Subunit of Retinal cGMP Phosphodiesterase

Hayashi¹,

Matsuura²,

Kachi³

et al. 2000

Journal of Biological Chemistry

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Retinal cGMP phosphodiesterase (PDE) is regulated by P␥, the regulatory subunit of PDE, and GTP/T␣, the GTP-bound ␣ subunit of transducin. In the accompanying paper (Matsuura, I., Bondarenko, V. A., Maeda, T., Kachi, S., Yamazaki, M., Usukura, J., Hayashi, F., and Yamazaki, A. (2000) J. Biol. Chem. 275, 32950 -32957), we have shown that all known P␥s contain a specific phosphorylation motif for cyclin-dependent protein kinase 5 (Cdk5) and that the unknown kinase is Cdk5 complexed with its activator. Here, using frog rod photoreceptor outer segments (ROS) isolated by a new method, we show that Cdk5 is involved in light-dependent P␥ phosphorylation in vivo. Under dark conditions only negligible amounts of P␥ were phosphorylated. However, under illumination that bleached less than 0.3% of the rhodopsin, ϳ4% of the total P␥ was phosphorylated in less than 10 s. P␥ dephosphorylation occurred in less than 1 s after the light was turned off. Analysis of the phosphorylated amino acid, inhibition of P␥ phosphorylation by Cdk inhibitors in vivo and in vitro, and twodimensional peptide map analysis of P␥ phosphorylated in vivo and in vitro indicate that Cdk5 phosphorylates a P␥ threonine in the same manner in vivo and in vitro. These observations, together with immunological data showing the presence of Cdk5 in ROS, suggest that Cdk5 is involved in light-dependent P␥ phosphorylation in ROS and that the phosphorylation is significant and reversible. In an homogenate of frog ROS, PDE activated by light/guanosine 5 -O-(3-thiotriphosphate) (GTP␥S) was inhibited by P␥ alone, but not by P␥ complexed with GDP/T␣ or GTP␥S/T␣. Under these conditions, P␥ phosphorylated by Cdk5 inhibited the light/ GTP␥S-activated PDE even in the presence of GTP␥S/ T␣. These observations suggest that phosphorylated P␥ interacts with and inhibits light/GTP␥S-activated PDE, but does not interact with GTP␥S/T␣ in the homogenate. Together, our results strongly suggest that after activation of PDE by light/GTP, P␥ is phosphorylated by Cdk5 and the phosphorylated P␥ inhibits GTP/T␣-activated PDE, even in the presence of GTP/T␣ in ROS.The hydrolysis of cGMP by PDE 1 in vertebrate ROS is directly involved in visual signal transduction (1, 2). The inactive PDE is composed of P␣␤, catalytic subunits, and two P␥s, regulatory subunits (3-6). In amphibian ROS, PDE is regulated similarly to that in mammalian ROS (7, 8): PDE catalytic activity is controlled by P␥ and GTP/T␣. In frog ROS membranes, bleached rhodopsin stimulates GTP/GDP exchange on T␣ (9), and the GTP/T␣ formed is released from membranebound T␤␥ (9, 10). The free GTP/T␣ interacts with P␣␤␥␥, and P␥ complexed with GTP/T␣ is released from P␣␤/membranes (10 -12). PDE is thereby activated. The release of the P␥ complex is detected even in an isotonic buffer containing Mg 2ϩ , and P␥ complexed with GTP␥S/T␣ can be isolated using sequential column chromatography (10). During PDE activation, P␥-less P␣␤ binds tightly to membranes. 2 In the recovery processes of frog ROS, after GTP hydrolysis by T␣, P␥ remai...

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Section: Methodsmentioning

confidence: 99%

Phosphorylation by Cyclin-dependent Protein Kinase 5 of the Regulatory Subunit of Retinal cGMP Phosphodiesterase

Hayashi¹,

Matsuura²,

Kachi³

et al. 2000

Journal of Biological Chemistry

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“…Full-length p35 contains 307 amino acids and the originally identified 25-kDa proteolytic fragment of p35 contains residues 99 -307. The 25-kDa proteolytic fragment is active in vivo (15,24) and in vitro when expressed in bacteria as a GST-fusion protein (26,32). A GST-fusion protein containing residues 109 -291 (designated as GST-p25 here) is also active as a Cdk5 activator (32).…”

Section: Identification Of Binding and Activating Domains Of The Cdk5mentioning

confidence: 99%

“…Cdk5 is able to phosphorylate tau on sites that are abnormally phosphorylated in Alzheimer's paired helical filaments (22,23). The 25-kDa subunit of the Cdk5 kinase (15,24) was later found to be a proteolytic fragment of a larger 35-kDa protein (p35) (14,25,26). An isoform of p35 that shares 57% amino acid identity to p35 has been identified, and its mRNA is predominantly expressed in the hippocampus (27).…”

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confidence: 99%

Identification of Functional Domains in the Neuronal Cdk5 Activator Protein

Poon

Lew

Hunter

1997

Journal of Biological Chemistry

103

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Cyclin-dependent kinase 5 (Cdk5) is activated by the neuronal-specific activator protein, p35. In contrast to the activation of typical CDKs by cyclin subunits, p35⅐Cdk5 was not further activated by the CDK-activating kinase (CAK) and was neither phosphorylated nor inhibited by the Tyr-15-specific Wee1 kinase. The previously identified proteolytic active fragment of p35, p25 (residues 91-307) as well as the slightly smaller fragment containing residues 109 -291, was found to be sufficient to bind and activate Cdk5. Other CDKs, including Cdk2, associated weakly with p25. However, their kinase activity was only activated to the low level observed for cyclin A⅐Cdk2 without Thr-160 phosphorylation, and phosphorylation of Thr-160 in Cdk2 did not activate the p25⅐Cdk2 complex further. We have identified distinct regions in p35 required for binding to Cdk5 or activation of Cdk5. Residues ϳ150 -200 of p35 were sufficient for binding to Cdk5, but residues ϳ279 -291 were needed in addition for activation of Cdk5 in vitro.Cyclins and cyclin-dependent kinases (CDKs) 1 are key regulators of the eukaryotic cell cycle (1). Cdc2 is associated with B-type cyclins and regulates M phase (2). Cdk2 is associated with A-and E-type cyclins, and the respective complexes are believed to control the S phase and G 1 -S transition, respectively (3, 4). Cdk4 and Cdk6 are associated with the D-type cyclins and are important for G 1 progression (3).The activity of CDKs is tightly regulated by an intricate system of protein-protein interaction and phosphorylation (5). The activation of CDKs, by definition, requires the association with cyclin partners. Full activation of CDKs requires in addition the phosphorylation of Thr-161/Thr-160, which lies in the activating T-loop in the crystal structure of Cdk2 (6, 7). The Thr-161/Thr-160 residue is phosphorylated by the CDK-activating kinase (CAK), which is composed of a cyclin H-Cdk7 complex and a RING finger protein subunit MAT1 (8). The activity of CDKs can be inhibited by phosphorylation of Thr-14 and Tyr-15 by the Wee1 and Myt1 protein kinases (9). Furthermore, CDKs can be inactivated by binding to CDK inhibitors like those from the p21 cip1/WAF1 family (p21 cip1/WAF1 , p27 kip1 , and p57 kip2 ) and the p16 INK4A family (p16 INK4A , p15 INK4B

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“…Like other members of the cyclin-dependent kinase family, cdk-5 activity requires association with a regulator, and recent studies have identified two homologous cdk-5 activators, p35 and p39flCksal (Ishiguro et al, 1994;Lew et al, 1994;Tsai et al, 1994;Tang et al, 1995). A further unrelated stimulator of cdk-5 activity, p67, which is identical to Munc-18, a component of synaptic vesicle fusion protein complexes, has also been described (Hata et al, 1993;Shetty et al, 1995).…”

mentioning

confidence: 99%

Cyclin D2 Interacts with cdk‐5 and Modulates Cellular cdk‐5/p35 Activity

Guidato

McLoughlin

Grierson

et al. 1998

Journal of Neurochemistry

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Cyclin-dependent kinase-5 (cdk-5) is a serine! threonine kinase that displays neurone-specific activity. Experimental manipulation of cdk-5 expression in neurones has shown that cdk-5 is essential for proper development of the nervous system and, in particular, for outgrowth of neurites. Such observations suggest that cdk-5 activity must be tightly controlled during development of the nervous system. To identify possible regulators of cdk-5, we used the yeast two-hybrid system to search for proteins that interact with cdk-5. In two independent yeast transformation events, cyclin D2 interacted with cdk-5. Immunoprecipitation experiments confirmed that cyclin D2 and cdk-5 interact in mammalian cells. Cyclin D2 did not activate cdk-5 as assayed using three different substrates, which was in contrast to a known cdk-5 activator, p35. However, cyclin D2 expression led to a decrease in cdk-5/p35 activity in transfected cells. As cyclin D2 and cdk-5 are known to share overlapping patterns of expression during development of the CNS, the results presented here suggest a role for cyclin D2 in modulating cdk-5 activity in postmitotic developing neurones. Key Words: Cyclin-dependent kinase-5 -p35-Cyclin D2 -Neurofilaments-Tau.

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Identification of the 23 kDa subunit of tau protein kinase II as a putative activator of cdk5 in bovine brain

Cited by 146 publications

References 37 publications

Phosphorylation by Cyclin-dependent Protein Kinase 5 of the Regulatory Subunit of Retinal cGMP Phosphodiesterase

Phosphorylation by Cyclin-dependent Protein Kinase 5 of the Regulatory Subunit of Retinal cGMP Phosphodiesterase

Identification of Functional Domains in the Neuronal Cdk5 Activator Protein

Cyclin D2 Interacts with cdk‐5 and Modulates Cellular cdk‐5/p35 Activity

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