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MBC in Press, published online ahead of print January 23, 2008
Mol. Biol. Cell 10.1091/mbc.E07-07-0730

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Submitted on August 1, 2007
Revised on December 26, 2007
Accepted on January 15, 2008

Spred1 and TESK1 - Two New Interaction Partners of the Kinase MARKK/TAO1 that Link the Microtubule and Actin Cytoskeleton

Cindy Johne, Dorthe Matenia, Xiao-yu Li, Thomas Timm, Kiruthiga Balusamy, and Eva-Maria Mandelkow

Max-Planck-Unit for Structural Molecular Biology, D-22607 Hamburg, Germany

Monitoring Editor: Paul Forscher

The signaling from MARKK/TAO1 to MARK/Par1 to phosphorylated MAPs renders microtubules dynamic and plays a role in neurite outgrowth or polarity development. Because hyperphosphorylation of Tau at MARK target sites is a hallmark of Alzheimer neurodegeneration we searched for upstream regulators by the yeast two-hybrid approach and identified two new interaction partners of MARKK, the regulator protein Spred1 and the kinase TESK1. Spred1-MARKK binding has no effect on the activity of MARKK and therefore does not change MT stability. Spred1-TESK1 binding causes inhibition of TESK1. Because TESK1 can phosphorylate cofilin and thus stabilizes F-actin stress fibers, the inhibition of TESK1 by Spred1 makes F-actin fibers dynamic. A third element in this interaction triangle is that TESK1 binds to and inhibits MARKK. Thus, in CHO cells the elevation of MARKK results in MT disruption (via activation of MARK/Par1 and phosphorylation of MAPs), but this can be blocked by TESK1. Similarly, enhanced TESK1-activity results in increased stress fibers (via phospho-cofilin), but this can be blocked by elevating Spred1. Thus, the three-way interaction between Spred1, MARKK, and TESK1 represents a pathway that links regulation of both the microtubule- and F-actin cytoskeleton.

Address correspondence to: Eva-Maria Mandelkow (mandelkow{at}mpasmb.desy.de)






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