Research

Molecular motors carry out vital functions in all eukaryotic cells. One of these, cytoplasmic dynein, is critical during mitosis, migration and cellular trafficking events. We are characterizing the pathways that impinge on dynein function. One pathway involves a kinase, CDK5, and two cytoplasmic dynein interacting proteins, LIS1 and NDEL1. CDK5 phosphorylates NDEL1 and regulates its interaction with dynein and LIS1. We have evidence that this pathway is a positive regulator of cytoplasmic dynein activity. A second pathway involves another kinase, GSK3. This kinase is best known for its inhibition by insulin signaling.

We find that GSK3 phosphorylates cytoplasmic dynein directly. This is an inhibitory event, leading to reduced NDEL1 binding and increased binding of cytoplasmic dynein to APC (adenomatous polyposis coli). Cancer-causing APC mutations that result in expression of a truncated APC protein disrupt this dynein-inhibitory pathway. We are currently investigating if and how these pathways cooperate to regulate motor activity in developing and mature neurons.

We are particularly interested in axonal transport of organelles and other cellular components, as disruption of this process occurs in a wide range of neurological disorders, including AD, ALS, Parkinson’s and Huntington’s diseases. Moreover, trafficking defects, in addition to the well-documented mitosis and migration defects, may contribute to a devastating childhood disorder caused by LIS1 haploinsufficiency (lissencephaly - smooth brain).

Publications

Chapman, DE, Reddy, BJN, Huy, B, Bovyn, MJ, Cruz, SJS, Al-Shammari, ZM, Han, H, Wang, W, Smith, DS, Gross, SP. (2019) Regulation of in vivo dynein force production by CDK5 and 14-3-3ε and KIAA0528, Nature Communications, 10, Article number: 228.

Hines, TJ, Gao, X, Sahu, S, Lange, MM, Turner, JR, Twiss, JL, Smith, DS. (2018). An essential postdevelopmental role for Lis1 in mice. eNeuro. Feb 2; 5(1).

Piroli, GG, Manuel, AM, Walla, MD, Shi, L, Patel, T, Lanci, SA, Wang, J, Gallloway, A, Ortinski, PI, Smith, DS, Frizzell, N. (2018). Identification of Novel Protein Targets of Dimethyl Fumarate Modification in Neurons and Astrocytes Reveals Actions Independent of Nrf2 Stabilization. Molecular & Cellular Proteomics, December 26 PMID: 30587509 DOI: 10.1074/mcp.RA118.000922

Shi L, Hines T, Bergson C, Smith D. (2018). Coupling of microtubule motors with AP-3 generated organelles in axons by NEEP21 Family Member Calcyon. Mol Biol Cell. 2018 Jun 27; PubMed PMID: 29949458

Sahoo, PK, Smith, DS, Perrone-Bizzozero, Twiss, JL. (2018). Axonal mRNA transport and translation at a glance. J Cell Sci  2018,131: jcs196808 doi: 10.1242/jcs.196808

Shi L, Muthusamy N, Smith D, Bergson C. (2017). Dynein binds and stimulates axonal motility of the endosome adaptor and NEEP21 family member, calcyon. Int J Biochem Cell Biol. Sep;90:93-102. PubMed PMID: 28734834; PubMed Central PMCID: PMC5774023

Gao FJ, Shi L, Hines T, Hebbar S, Neufeld KL, Smith DS (2017). Insulin signaling regulates a functional interaction between Adenomatous Polyposis Coli (APC) and cytoplasmic dynein. Molecular Biology of the Cell. Jan 5. Link to paper and PubMed link

Gao FJ, Hebbar S, Gao XA, Alexander M, Pandey JP, Walla MD, Cotham WE, King SJ, Smith DS (2015). GSK-3β Phosphorylation of Cytoplasmic Dynein Reduces Ndel1 Binding to Intermediate Chains and Alters Dynein Motility. Traffic. 2015 Sep;16(9):941-61. Link to paper and PubMed link

Pandey JP, Smith DS (2011). A Cdk5-dependent switch regulates Lis1/Ndel1/dynein-driven organelle transport in adult axons. (2011). Journal of Neuroscience. Nov 23;31(47):17207-19. Link to paper and PubMed link

Hebbar S, Mesngon MT, Guillotte AM, Desai B, Ayala R, Smith DS (2008). Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells. Journal of Cell Biology. Sep 22;182(6):1063-71. Link to paper

Hebbar S, Guillotte AM, Mesngon MT, Zhou Q, Wynshaw-Boris A, Smith DS (2008). Genetic enhancement of the Lis1+/- phenotype by a heterozygous mutation in the adenomatous polyposis coli gene. Developmental Neuroscience. 30(1-3):157-70. Link to paper

Willis DE, van Niekerk EA, Sasaki Y, Mesngon M, Merianda TT, Williams GG, Kendall M, Smith DS, Bassell GJ, Twiss JL (2007) Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs. Journal of Cell Biology. Sep 10;178(6):965-80. Link to paper

Mesngon MT, Tarricone C, Hebbar S, Guillotte AM, Schmitt EW, Lanier L, Musacchio A, King SJ, Smith DS (2006). Regulation of cytoplasmic dynein ATPase by Lis1. Journal of Neuroscience. Feb 15;26(7):2132-9. Link to paper

Smith, DS (2003). Cdk5 in neuroskeletal dynamics. Neurosignals. Sep-Oct;12(4-5):239-51. Link to paper

Smith DS, Tsai LH (2002). Cdk5 behind the wheel: a role in trafficking and transport? Trends in Cell Biology. Jan;12(1):28-36. Link to paper

Smith DS, Greer PL, Tsai LH (2001). Cdk5 on the brain. Cell Growth and Differentiation. Jun;12(6):277-83. Link to paper

Niethammer M*, Smith DS*, Ayala R, Peng J, Ko J, Lee MS, Morabito M, Tsai LH (2000). NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron. Dec;28(3):697-711. *authors contributed equally. Link to paper

Smith DS, Leone G, DeGregori J, Ahmed MN, Qumsiyeh MB, Nevins JR (2000). Induction of DNA replication in adult rat neurons by deregulation of the retinoblastoma/E2F G1 cell cycle pathway. Cell Growth and Differentiation. Dec;11(12):625-33. Link to paper

Smith DS, Niethammer M, Ayala R, Zhou Y, Gambello MJ, Wynshaw-Boris A, Tsai LH (2000). Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nature Cell Biology. Nov;2(11):767-75. Link to paper

Twiss JL, Smith DS, Chang B, Shooter EM (2000).Translational control of ribosomal protein L4 mRNA is required for rapid neurite regeneration. Neurobiology of Disease. Aug;7(4):416-28.

Hess DT, Smith DS, Patterson SI, Kahn RA, Skene JH, Norden JJ (1999). Rapid arrest of axon elongation by brefeldin A: a role for the small GTP-binding protein ARF in neuronal growth cones. Journal of Neurobiology. Jan;38(1):105-15. Link to paper

Smith DS, Skene JH (1997). A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. Journal of Neuroscience. Jan 15;17(2):646-58. Link to paper

Hess DT, Patterson SI, Smith DS, Skene JH (1993). Neuronal growth cone collapse and inhibition of protein fatty acylation by nitric oxide. Nature. Dec 9;366(6455):562-5. Link to paper

Landreth GE, Smith DS, McCabe C, Gittinger C (1990). Characterization of a Nerve Growth Factor-Stimulated Protein Kinase in PC12 Cells Which Phosphorylates Microtubule-Associated Protein 2 and pp250. Journal Of Neurochemistry. Aug;55(2):514-23. Link to paper

Smith DS, King CS, Pearson E, Gittinger CK, Landreth GE (1989). Selective-inhibition of nerve growth factor-stimulated protein-kinases by k-252a and 5'-s-methyladenosine in pc12 cells. Journal Of Neurochemistry. Sep;53(3):800-806. Link to paper