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Protein–Protein Interactions Involving the N-Terminus of p35

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Cyclin Dependent Kinase 5 (Cdk5)

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Abstract

As a major regulator of Cdk5, the protein p35 exerts various effects on neuronal cells. Under certain conditions, p35 undergoes truncation of its N-terminus to form the protein p25. Although p25 is equally potent in activating Cdk5 as p35, it displays a number of differences from the latter, indicating an indispensable role of the N-terminal region for carrying out many of the Cdk5-p35 activities. A number of proteins have been identified that interact with p35 via its N-terminus. Such binding confers p35 and Cdk5 a multitude of properties, including regulation of Cdk5 activity by interacting with the proteins SET, CK2, importins β, 5 and 7, as well as the microtubule cytoskeleton; mediation of nuclear import of p35 through binding with the importin proteins; and participation in the control of protein biogenesis by regulating ribosomal protein S6 kinase 1. p35 itself also functions as a microtubule-associated protein through its N-terminus to regulate microtubule dynamics which is required for neurite outgrowth. Therefore, the discovery of p35–N-terminal binding partners has facilitated the elucidation of p35 and Cdk5 functions and regulations.

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References

  1. Lew, J., Q. Q. Huang, Z. Qi, R. J. Winkfein, R. Aebersold, T. Hunt, and J. H. Wang (1994) A brain-specific activator of cyclin-dependent kinase 5. Nature 371:423–426

    Article  PubMed  CAS  Google Scholar 

  2. Tang, D., A. C. Chun, M. Zhang, and J. H. Wang (1997) Cyclin-dependent kinase 5 (Cdk5) activation domain of neuronal Cdk5 activator: Evidence of the existence of cyclin fold in neuronal Cdk5a activator. J. Biol. Chem. 272:12318–12327

    CAS  Google Scholar 

  3. Tsai, L. H., I. Delalle, V. S. Caviness, Jr., T. Chae, and E. Harlow (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371:419–423

    Article  PubMed  CAS  Google Scholar 

  4. Tsai, L. H., T. Takahashi, V. S. Caviness, Jr., and E. Harlow (1993) Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development 119:1029–1040

    PubMed  CAS  Google Scholar 

  5. Poon, R. Y., J. Lew, and T. Hunter (1997) Identification of functional domains in the neuronal Cdk5 activator protein. J. Biol. Chem. 272:5703–5708

    CAS  Google Scholar 

  6. Ohshima, T., J. M. Ward, C. G. Huh, G. Longenecker, Veeranna, H. C. Pant, R. O. Brady, L. J. Martin, and A. B. Kulkarni (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl. Acad. Sci. USA 93:11173–11178

    Article  CAS  Google Scholar 

  7. Chae, T., Y. T. Kwon, R. Bronson, P. Dikkes, E. Li, and L. H. Tsai (1997) Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18:29–42

    Article  PubMed  CAS  Google Scholar 

  8. Ko, J., S. Humbert, R. T. Bronson, S. Takahashi, A. B. Kulkarni, E. Li, and L. H. Tsai (2001) p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J. Neurosci. 21:6758–6771

    CAS  Google Scholar 

  9. Kusakawa, G., T. Saito, R. Onuki, K. Ishiguro, T. Kishimoto, and S. Hisanaga (2000) Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25. J. Biol. Chem. 275:17166–17172

    CAS  Google Scholar 

  10. Lee, M. S., Y. T. Kwon, M. Li, J. Peng, R. M. Friedlander, and L. H. Tsai (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364

    Article  PubMed  CAS  Google Scholar 

  11. Patrick, G. N., L. Zukerberg, M. Nikolic, M. S. de la, P. Dikkes, and L. H. Tsai (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622

    Article  PubMed  CAS  Google Scholar 

  12. Cruz, J. C., H. C. Tseng, J. A. Goldman, H. Shih, and L. H. Tsai (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471–483

    Article  PubMed  CAS  Google Scholar 

  13. Nguyen, M. D., R. C. Lariviere, and J. P. Julien (2001) Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron 30:135–147

    Article  PubMed  CAS  Google Scholar 

  14. Lee, K. Y., J. L. Rosales, D. Tang, and J. H. Wang (1996) Interaction of cyclin-dependent kinase 5 (Cdk5) and neuronal Cdk5 activator in bovine brain. J. Biol. Chem. 271:1538–1543

    CAS  Google Scholar 

  15. Qi, Z., Q. Q. Huang, K. Y. Lee, J. Lew, and J. H. Wang (1995) Reconstitution of neuronal Cdc2-like kinase from bacteria-expressed Cdk5 and an active fragment of the brain-specific activator. Kinase activation in the absence of Cdk5 phosphorylation. J. Biol. Chem. 270:10847–10854

    CAS  Google Scholar 

  16. Sasaki, Y., C. Cheng, Y. Uchida, O. Nakajima, T. Ohshima, T. Yagi, M. Taniguchi, T. Nakayama, R. Kishida, Y. Kudo, S. Ohno, F. Nakamura, and Y. Goshima (2002) Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. Neuron 35:907–920

    Article  PubMed  CAS  Google Scholar 

  17. Zukerberg, L. R., G. N. Patrick, M. Nikolic, S. Humbert, C. L. Wu, L. M. Lanier, F. B. Gertler, M. Vidal, R. A. Van Etten, and L. H. Tsai (2000) Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26:633–646

    Article  PubMed  CAS  Google Scholar 

  18. Lee, M. H., M. Nikolic, C. A. Baptista, E. Lai, L. H. Tsai, and J. Massague (1996) The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons. Proc. Natl. Acad. Sci. USA 93:3259–3263

    Article  CAS  Google Scholar 

  19. Fu, X., Y. K. Choi, D. Qu, Y. Yu, N. S. Cheung, and R. Z. Qi (2006) Identification of nuclear import mechanisms for the neuronal CDK5 activator. J. Biol. Chem. 281:39014–39021

    CAS  Google Scholar 

  20. Lim, A. C., Z. Hou, C. P. Goh, and R. Z. Qi (2004) Protein kinase CK2 is an inhibitor of the neuronal Cdk5 kinase. J. Biol. Chem. 279:46668–46673

    CAS  Google Scholar 

  21. Hou, Z., Q. Li, L. He, H. Y. Lim, X. Fu, N. S. Cheung, D. X. Qi, and R. Z. Qi (2007) Microtubule association of the neuronal p35 activator of Cdk5. J. Biol. Chem. 282:18666–18670

    CAS  Google Scholar 

  22. Qu, D., Q. Li, H. Y. Lim, N. S. Cheung, R. Li, J. H. Wang, and R. Z. Qi (2002) The protein SET binds the neuronal Cdk5 activator p35nck5a and modulates Cdk5/p35nck5a activity. J. Biol. Chem. 277:7324–7332

    CAS  Google Scholar 

  23. Gong, X., X. Tang, M. Wiedmann, X. Wang, J. Peng, D. Zheng, L. A. Blair, J. Marshall, and Z. Mao (2003) Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38:33–46

    Article  PubMed  CAS  Google Scholar 

  24. Nikolic, M., H. Dudek, Y. T. Kwon, Y. F. Ramos, and L. H. Tsai (1996) The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 10:816–825

    Article  PubMed  CAS  Google Scholar 

  25. Gorlich, D. and U. Kutay (1999) Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell Dev. Biol. 15:607–660

    CAS  Google Scholar 

  26. Dufner, A. and G. Thomas (1999) Ribosomal S6 kinase signaling and the control of translation. Exp. Cell Res. 253:100–109

    Article  CAS  Google Scholar 

  27. Martin, K. A. and J. Blenis (2002) Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv. Cancer Res. 86:1–39

    Article  CAS  Google Scholar 

  28. Hou, Z., L. He, and R. Z. Qi (2007) Regulation of s6 kinase 1 activation by phosphorylation at ser-411. J. Biol. Chem. 282:6922–6928

    CAS  Google Scholar 

  29. Schalm, S. S., A. R. Tee, and J. Blenis (2005) Characterization of a conserved C-terminal motif (RSPRR) in ribosomal protein S6 kinase 1 required for its mammalian target of rapamycin-dependent regulation. J. Biol. Chem. 280:11101–11106

    CAS  Google Scholar 

  30. Kandel, E. R. (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294:1030–1038

    Article  PubMed  CAS  Google Scholar 

  31. Steward, O. and E. M. Schuman (2001) Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 24:299–325

    CAS  Google Scholar 

  32. Hay, N. and N. Sonenberg (2004) Upstream and downstream of mTOR. Genes Dev. 18:1926–1945

    Article  PubMed  CAS  Google Scholar 

  33. Baumann, K., E. M. Mandelkow, J. Biernat, H. Piwnica-Worms, and E. Mandelkow (1993) Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 336:417–424

    Article  PubMed  CAS  Google Scholar 

  34. Paudel, H. K., J. Lew, Z. Ali, and J. H. Wang (1993) Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments. J. Biol. Chem. 268:23512–23518

    CAS  Google Scholar 

  35. Tanaka, T., F. F. Serneo, H. C. Tseng, A. B. Kulkarni, L. H. Tsai, and J. G. Gleeson (2004) Cdk5 phosphorylation of doublecortin Ser297 regulates its effect on neuronal migration. Neuron 41:215–227

    Article  PubMed  CAS  Google Scholar 

  36. Kamei, H., T. Saito, M. Ozawa, Y. Fujita, A. Asada, J. A. Bibb, T. C. Saido, H. Sorimachi, and S. Hisanaga (2007) Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J. Biol. Chem. 282:1687–1694

    CAS  Google Scholar 

  37. Patrick, G. N., P. Zhou, Y. T. Kwon, P. M. Howley, and L. H. Tsai (1998) p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. J. Biol. Chem. 273:24057–24064

    CAS  Google Scholar 

  38. He, L., Z. Hou, and R. Z. Qi; unpublished data

    Google Scholar 

  39. Harada, T., T. Morooka, S. Ogawa, and E. Nishida (2001) ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nat. Cell Biol. 3:453–459

    CAS  Google Scholar 

  40. Paglini, G., G. Pigino, P. Kunda, G. Morfini, R. Maccioni, S. Quiroga, A. Ferreira, and A. Caceres (1998) Evidence for the participation of the neuron-specific CDK5 activator P35 during laminin-enhanced axonal growth. J. Neurosci. 18:9858–9869

    CAS  Google Scholar 

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Acknowledgments

This work was supported by the Earmarked Research Grant from the Research Grants Council and the Area of Excellence Scheme under the University Grants Committee of Hong Kong.

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Authors and Affiliations

  1. Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Robert Z. Qi

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  1. Gary Kar Ho Ng
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  2. Lisheng He
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  3. Robert Z. Qi
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Correspondence to Robert Z. Qi .

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Editors and Affiliations

  1. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Nancy Y. Ip

  2. Department of Brain and Cognitive Science, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 02139, Cambridge, MA, USA

    Li-Huei Tsai

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Ng, G.K.H., He, L., Qi, R.Z. (2008). Protein–Protein Interactions Involving the N-Terminus of p35. In: Ip, N.Y., Tsai, LH. (eds) Cyclin Dependent Kinase 5 (Cdk5). Springer, Boston, MA. https://doi.org/10.1007/978-0-387-78887-6_12

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