Kinesin heavy chain

EVOLUTIONARY HOMOLOGS

Seven literature reviews of Kinesin function are freely available online:

• Endow, S. A. (2000). Molecular motors - a paradigm for mutant analysis. J. Cell Sci. 113: 1311-1318

• Hunter, A. W. and Wordeman, L. (2000). How motor proteins influence microtubule polymerization dynamics. J. Cell Sci. 113: 4379-89

• Kim, A. J. and Endow, S. A. (2000). A kinesin family tree. J. Cell Sci. 113 : 3681-2

• Goldstein, L. S. (2001). Kinesin molecular motors: transport pathways, receptors, and human disease. Proc. Natl. Acad. Sci. 98(13): 6999-7003

• Hepler, P. K., Valster, A., Molchan, T. and Vos, J. W. (2002). Roles for kinesin and myosin during cytokinesis. Philos. Trans. R Soc. Lond. B Biol. Sci. 357(1422): 761-6

• Thomas, N., Imafuku, Y., Kamiya, T. and Tawada, K. (2003). Kinesin: a molecular motor with a spring in its step. Proc. R. Soc. Lond. B Biol. Sci. 269(1507): 2363-71

• Schnapp, B. J. (2003). Trafficking of signaling modules by kinesin motors . J. Cell Sci. 116: 2125-2135

Articles about kinesin biology available online:

• Hancock, W. O. and Howard, J. (1999). Kinesin's processivity results from mechanical and chemical coordination between the ATP hydrolysis cycles of the two motor domains. Proc. Natl. Acad. Sci. 96: 13147-52

• Okada, Y. and Hirokawa, N. (2000). Mechanism of the single-headed processivity: Diffusional anchoring between the K-loop of kinesin and the C terminus of tubulin. Proc. Natl. Acad. Sci. 97: 640-645

• Xing, J., et al. (2000). Kinesin has three nucleotide-dependent conformations. Implications for strain-dependent release. J. Biol. Chem. 275: 35413-35423

• Yabe, J. T., Pimenta, A., and Shea, T. B. (1999). Kinesin-mediated transport of neurofilament protein oligomers in growing axons. J. Cell Sci. 112: 3799-3814

• Xia, C. H., Roberts, E. A., Her, L. S., Liu, X., Williams, D. S., Cleveland, D. W. and Goldstein, L. (2003). Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. J. Cell Biol. 161(1): 55-66

Kinesin and gastrulation

In Xenopus, axis development is initiated by dorsally elevated levels of cytoplasmic ß-catenin, an intracellular factor regulated by GSK3 kinase activity. Upon fertilization, factors that increase ß-catenin stability are translocated to the prospective dorsal side of the embryo in a microtubule-dependent process. However, neither the identity of these factors nor the mechanism of their movement is understood. The GSK3 inhibitory protein GBP/Frat is shown to bind kinesin light chain (KLC), a component of the microtubule motor kinesin. Upon egg activation, GBP-GFP and KLC-GFP form particles and exhibit directed translocation. KLC, through a previously uncharacterized conserved domain, binds a region of GBP that is required for GBP translocation and for GSK3 binding, and competes with GSK3 for GBP. A model is proposed in which conventional kinesin transports a GBP-containing complex to the future dorsal side, where GBP dissociates and contributes to the local stabilization of ß-catenin by binding and inhibiting GSK3 (Weaver, 2003).

The formation of the dorsoanterior axis in Xenopus is dependent upon a series of events that occur during the first cell cycle after fertilization. Sperm entry initiates a rotation of the peripheral layer of the egg, called the cortex, relative to the inner core cytoplasm. This event, called cortical rotation, results in a 30° displacement of the vegetal cortex toward the future dorsoanterior region. Cortical rotation coincides with the translocation of a 'dorsalizing activity' that also moves from the vegetal pole up toward the prospective dorsal side of the embryo. Translocation of the dorsalizing activity is both necessary and sufficient for the formation of the Spemann organizer, which regulates the formation of the embryonic axes during the gastrula stages (Weaver, 2003 and references therein).

Although the molecular identity of the dorsal determinants is not clear, it is known that their translocation leads to the dorsal accumulation of ß-catenin, which then activates the expression of dorsal organizer genes at the onset of zygotic transcription. Cytoplasmic transplant experiments using ß-catenin-depleted embryos have shown that ß-catenin is not the endogenous dorsalizing activity, but that instead this activity probably consists of proteins involved in ß-catenin stabilization. ß-catenin is normally phosphorylated by the serine-threonine kinase glycogen synthase kinase 3 (GSK3) within a protein complex that also includes Axin and the adenomatous polyposis coli gene product (APC), and this phosphorylation targets ß-catenin for degradation by the ubiquitin-proteosome pathway. Work from many laboratories has led to a model in which the localized inhibition of GSK3 in the dorsal region causes the dorsal accumulation of ß-catenin. How GSK3 becomes locally inhibited by the dorsal determinants, however, is still an open question (Weaver, 2003).

A strong candidate component of the translocating dorsalizing activity is GBP, a vertebrate-specific GSK3-binding protein. Depletion of endogenous GBP from the embryo with antisense oligonucleotides causes a loss of dorsal axial structures, showing that GBP is required for dorsal axis formation. GBP inhibits GSK3 activity by preventing its binding to Axin, thus preventing GSK3 from phosphorylating ß-catenin. When microinjected ventrally, GBP mimics the endogenous dorsal signal and induces the formation of a secondary dorsal axis, and overexpression of GBP also leads to GSK3 degradation in the cortical shear zone. In addition to binding GSK3, GBP also binds directly to Dsh, a positive effector of the canonical Wnt signaling pathway. Together, these two proteins potently synergize to stabilize ß-catenin (Weaver, 2003).

Thus, both GBP and its binding partner Dsh have characteristics that strongly suggest that they are part of the endogenous dorsalizing activity. Furthermore, Dsh-GFP has been shown to form particles in the shear zone that exhibit directed movement on microtubules, and endogenous Dsh accumulates dorsally by the end of cortical rotation. However, no direct molecular link has yet been established between either GBP or Dsh and the microtubule array. In this study, it has been demonstrated that GBP binds kinesin light chain (KLC), a component of the plus end-directed microtubule motor kinesin. Like Dsh, GBP-GFP and KLC-GFP form particles that exhibit fast, directional translocation in the shear zone during the period of cortical rotation. These results suggest a model in which GBP acts initially as a link between the transport apparatus and the dorsalizing activity, and subsequently as an inhibitor of GSK3 in the ß-catenin degradation complex (Weaver, 2003).

Kinesin-mediated transport of Smad2 is required for signaling in response to TGF-beta ligands

During vertebrate development, Activin/Nodal-related ligands signal through Smad2, leading to its activation and accumulation in the nucleus. This study demonstrates that Smad2 constantly shuttles between the cytoplasm and nucleus both in early Xenopus embryo explants and in living zebrafish embryos, providing a mechanism whereby the intracellular components of the pathway constantly monitor receptor activity. An intact microtubule network and kinesin ATPase activity are required for Smad2 phosphorylation and nuclear accumulation in response to Activin/Nodal in early vertebrate embryos and TGF-β in mammalian cells. The kinesin involved is kinesin-1, and Smad2 interacts with the kinesin-1 light chain subunit. Interfering with kinesin activity in Xenopus and zebrafish embryos phenocopies loss of Nodal signaling. These results reveal that kinesin-mediated transport of Smad2 along microtubules to the receptors is an essential step in ligand-induced Smad2 activation (Batut, 2007).

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