Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Cyclin-Dependent Kinase 5 (Cdk5) Modulates Signal Transduction Pathways Regulating Neuronal Survival

  • Chapter
  • First Online:
Cyclin Dependent Kinase 5 (Cdk5)

Abstract

Cyclin-dependent kinase 5 (Cdk5) in the nervous system has evolved to become a “surveillance system” that, among its other functions, monitors and integrates fluctuations in the activities of signaling cascades involved in nervous system growth, differentiation, and survival. In this review, we have focused primarily on Cdk5 cross talk and neuronal survival conducted in our laboratory. Cdk5 activity is tightly regulated in the nervous system, but may be deregulated under neuronal stress such as oxidative injury, excitotoxic stimulations, and β-amyloid exposure resulting in apoptosis marked by aggregates of hyperphosphorylated Tau, neurofilament, and other cytoskeletal proteins. We have demonstrated that Cdk5 modulates mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK3), and phosphoinositol-3-kinase/protein kinase B (PI3 K/Akt). In addition, it is shown that Cdk5 directly and indirectly mediates the Ras guanine nucleotide exchange factors-1/2 (RasGRF1/2) and glycogen synthase kinase 3β (GSK3β) signaling pathways, respectively.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahuja HS, Zhu Y, Zakeri Z (1997) Association of cyclin-dependent kinase 5 and its activator p35 with apoptotic cell death. Dev Genet 21:258–267.

    Article  PubMed  CAS  Google Scholar 

  • Angelo M, Plattner F, Giese KP (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J Neurochem 99:353–370.

    Article  PubMed  CAS  Google Scholar 

  • Anton ES, Marchionni MA, Lee KF, Rakic P (1997) Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development 124:3501–3510.

    PubMed  CAS  Google Scholar 

  • Bearer EL, Breakefield XO, Schuback D, Reese TS, LaVail JH (2000) Proc Natl Acad Sci USA 97:8146–8150.

    Article  CAS  Google Scholar 

  • Brady ST, Lasek RJ, Allen RD (1985) Videomicroscopy of fast axonal transport in extruded axoplasm: A new model for study of molecular mechanisms. Cell Motil 5:81–101.

    Article  PubMed  CAS  Google Scholar 

  • Brady ST, Pfister KK, Bloom GS (1990) A monoclonal antibody against kinesin inhibits both anterograde and retrograde fast axonal transport in squid axoplasm. Proc Natl Acad Sci USA 87:1061–1065.

    Article  CAS  Google Scholar 

  • Burden S, Yarden Y (1997) Neuregulins and their receptors: a versatile signaling module in organogenesis and oncogenesis. Neuron 18:847–855.

    Article  PubMed  CAS  Google Scholar 

  • Cheung EC, Slack RS (2004) Emerging role for ERK as a key regulator of neuronal apoptosis. Sci STKE 2004:PE45.

    Google Scholar 

  • Cruz JC, Tsai LH (2004) A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 14:390–394.

    Article  PubMed  CAS  Google Scholar 

  • Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471–483.

    Article  PubMed  CAS  Google Scholar 

  • Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927.

    Article  PubMed  CAS  Google Scholar 

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241.

    Article  PubMed  CAS  Google Scholar 

  • Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025–1037.

    Article  PubMed  CAS  Google Scholar 

  • Dong Z, Brennan A, Liu N, Yarden Y, Lefkowitz G, Mirsky R, Jessen KR (1995) Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron 15:585–596.

    Article  PubMed  CAS  Google Scholar 

  • Eilers A, Whitfield J, Babij C, Rubin LL, Ham J (1998) Role of the Jun kinase pathway in the regulation of c-Jun expression and apoptosis in sympathetic neurons. J Neurosci 18:1713–1724.

    PubMed  CAS  Google Scholar 

  • Fischer A, Sananbenesi F, Spiess J, Radulovic J (2003) Cdk5: a novel role in learning and memory. Neurosignals 12:200–208.

    Article  PubMed  CAS  Google Scholar 

  • Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825–838.

    Article  PubMed  CAS  Google Scholar 

  • Fu AK, Fu WY, Cheung J, Tsim KW, Ip FC, Wang JH, Ip NY (2001) Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat Neurosci 4:374–381.

    Article  PubMed  CAS  Google Scholar 

  • Gassmann M, Lemke G (1997) Neuregulins and neuregulin receptors in neural development. Curr Opin Neurobiol 7:87–92.

    Article  PubMed  CAS  Google Scholar 

  • Grewal SS, York RD, Stork PJ (1999) Extracellular-signal-regulated kinase signalling in neurons. Curr Opin Neurobiol 9:544–553.

    Article  PubMed  CAS  Google Scholar 

  • Guo Q (2003) Cyclin-dependent kinase 5–a neuronal killer? Sci Aging Knowledge Environ 2003:pe36.

    Google Scholar 

  • Gupta S, Campbell D, Derijard B, Davis RJ (1995) Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267:389–393.

    Article  PubMed  CAS  Google Scholar 

  • Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, Davis RJ (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. Embo J 15:2760–2770.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kanungo J, Li BS, Zheng Y, Pant HC (2006) Cyclin-dependent kinase 5 influences Rohon-Beard neuron survival in zebrafish. J Neurochem 99:251–259.

    Article  PubMed  CAS  Google Scholar 

  • Kanungo J, Li BS, Goswami M, Zheng YL, Ramchandran R, Pant HC (2007) Cloning and characterization of zebrafish (Danio rerio) cyclin-dependent kinase 5. Neurosci Lett 412:233–238.

    Article  PubMed  CAS  Google Scholar 

  • Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN, Hay N (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev 11:701–713.

    Article  PubMed  CAS  Google Scholar 

  • Kesavapany S, Pareek TK, Zheng YL, Amin N, Gutkind JS, Ma W, Kulkarni AB, Grant P, Pant HC (2006) Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor-1. Neurosignals 15:157–173.

    Article  PubMed  CAS  Google Scholar 

  • Kesavapany S, Amin N, Zheng YL, Nijhara R, Jaffe H, Sihag R, Gutkind JS, Takahashi S, Kulkarni A, Grant P, Pant HC (2004) p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (RasGRF2) mediates Rac-dependent extracellular signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons. J Neurosci 24:4421–4431.

    Article  PubMed  CAS  Google Scholar 

  • Ko J, Humbert S, Bronson RT, Takahashi S, Kulkarni AB, Li E, Tsai LH (2001) p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J Neurosci 21:6758–6771.

    PubMed  CAS  Google Scholar 

  • Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22:667–676.

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR (1994) The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369:156–160.

    Article  PubMed  CAS  Google Scholar 

  • Li BS, Zhang L, Takahashi S, Ma W, Jaffe H, Kulkarni AB, Pant HC (2002) Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3. Embo J 21:324–333.

    Article  PubMed  CAS  Google Scholar 

  • Li BS, Ma W, Jaffe H, Zheng Y, Takahashi S, Zhang L, Kulkarni AB, Pant HC (2003) Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem 278:35702–35709.

    Article  PubMed  CAS  Google Scholar 

  • Martin JH, Mohit AA, Miller CA (1996) Developmental expression in the mouse nervous system of the p493F12 SAP kinase. Brain Res Mol Brain Res 35:47–57.

    Article  PubMed  CAS  Google Scholar 

  • Moran CM, Donnelly M, Ortiz D, Pant HC, Mandelkow EM, Shea TB (2005) Cdk5 inhibits anterograde axonal transport of neurofilaments but not that of tau by inhibition of mitogen-activated protein kinase activity. Brain Res Mol Brain Res 134:338–344.

    Article  PubMed  CAS  Google Scholar 

  • Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. Embo J 21:281–293.

    Article  PubMed  CAS  Google Scholar 

  • Morfini G, Szebenyi G, Brown H, Pant HC, Pigino G, DeBoer S, Beffert U, Brady ST (2004) A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. Embo J 23:2235–2245.

    Article  PubMed  CAS  Google Scholar 

  • Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, Brady RO, Martin LJ, Kulkarni AB (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.

    Google Scholar 

  • O’Hare MJ, Kushwaha N, Zhang Y, Aleyasin H, Callaghan MS, Slack RS, Albert PR, Vincent I, Park DS (2005) Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotoc and excitotoxic neuronal death. J Neurosci 25:8954–8966.

    Article  PubMed  Google Scholar 

  • Penaloza C, Lin L, Lockshin RA, Zakeri Z (2006) Cell death in development: shaping the embryo. Histochem Cell Biol 126:149–158.

    Article  PubMed  CAS  Google Scholar 

  • Ratner N, Bloom GS, Brady ST (1998) A role for Cdk5 kinase in fast anterograde axonal transport: novel effects of olomoucine and the APC tumor suppressor protein. J Neurosci 18:7717–7726.

    PubMed  CAS  Google Scholar 

  • Rio C, Rieff HI, Qi P, Khurana TS, Corfas G (1997) Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron 19:39–50.

    Article  PubMed  CAS  Google Scholar 

  • Shah NM, Marchionni MA, Isaacs I, Stroobant P, Anderson DJ (1994) Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell 77:349–360.

    Article  PubMed  CAS  Google Scholar 

  • Sharma P, Barchi Jr. JJ, Huang X, Amin ND, Jaffe H, Pant HC (1998) Site-specific phosphorylation of Lys-Ser-Pro repeat peptides from neurofilament H by cyclin-dependent kinase 5: structural basis for substrate recognition. Biochemistry 37:4759–4766.

    Article  PubMed  CAS  Google Scholar 

  • Sharma P, Veeranna, Sharma M, Amin ND, Sihag RK, Grant P, Ahn N, Kulkarni AB, Pant HC (2002) Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. J Biol Chem 277:528–534.

    Google Scholar 

  • Sheetz MP, Vale R, Schnapp B, Schroer T, Reese TS (1986) Vesicle movements and microtubule-based motors. J Cell Sci 5:181–188

    CAS  Google Scholar 

  • Shetty KT, Link WT, Pant HC (1993) cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation and characterization. Proc Natl Acad Sci USA 90:6844–6848.

    Article  PubMed  CAS  Google Scholar 

  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39.

    Article  PubMed  CAS  Google Scholar 

  • Stephens L, Eguinoa A, Corey S, Jackson T, Hawkins PT (1993) Receptor stimulated accumulation of phosphatidylinositol (3,4,5)-trisphosphate by G-protein mediated pathways in human myeloid derived cells. Embo J 12:2265–2273.

    PubMed  CAS  Google Scholar 

  • Takahashi S, Saito T, Hisanaga S, Pant HC, Kulkarni AB (2003) Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules. J Biol Chem 278:10506–10515.

    Article  PubMed  CAS  Google Scholar 

  • Veeranna, Amin ND, Ahn NG, Jaffe H, Winters CA, Grant P, Pant HC (1998) Mitogen-activated protein kinases (Erk1,2) phosphorylate Lys-Ser-Pro (KSP) repeats in neurofilament proteins NF-H and NF-M. J Neurosci 18:4008–4021.

    Google Scholar 

  • Weishaupt JH, Neusch C, Bahr M (2003) Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell Tissue Res 312:1–8.

    PubMed  CAS  Google Scholar 

  • Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Rakic P, Flavell RA (1997) Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389:865–870.

    Article  PubMed  CAS  Google Scholar 

  • Zhang Q, Ahuja HS, Zakeri ZF, Wolgemuth DJ (1997) Cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. Dev Biol 183:222–233.

    Article  PubMed  CAS  Google Scholar 

  • Zheng YL, Li BS, Kanungo J, Kesavapany S, Amin N, Grant P, Pant HC (2007) Cdk5 Modulation of mitogen-activated protein kinase signaling regulates neuronal survival. Mol Biol Cell 18:404–413.

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Lin L, Kim S, Quaglino D, Lockshin RA, Zakeri Z (2002) Cyclin dependent kinase 5 and its interacting proteins in cell death induced in vivo by cyclophosphamide in developing mouse embryos. Cell Death Differ 9:421–430.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20814, USA

    Harish C. Pant

Authors
  1. Parvathi Rudrabhatla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jyotshna Kanungo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ya-Li Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Niranjana D. Amin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sashi Kesavapany
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Harish C. Pant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harish C. Pant .

Editor information

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

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Rudrabhatla, P., Kanungo, J., Zheng, YL., Amin, N.D., Kesavapany, S., Pant, H.C. (2008). Cyclin-Dependent Kinase 5 (Cdk5) Modulates Signal Transduction Pathways Regulating Neuronal Survival. 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_6

Download citation

Publish with us

Policies and ethics

Search

Navigation