Spred1 and TESK1--two new interaction partners of the kinase MARKK/TAO1 that link the microtubule and actin cytoskeleton.
The signaling from MARKK/TAO1 to the MAP/microtubule affinity-regulating kinase MARK/Par1 to phosphorylated microtubule associated proteins (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 regulatory Sprouty-related protein with EVH-1 domain1 (Spred1) and the testis-specific protein kinase (TESK1). Spred1-MARKK binding has no effect on the activity of MARKK; therefore, it does not change microtubule (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 Chinese hamster ovary (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.
Johne
Cindy
C
Max-Planck-Unit for Structural Molecular Biology, D-22607 Hamburg, Germany.
Matenia
Dorthe
D
Li
Xiao-Yu
XY
Timm
Thomas
T
Balusamy
Kiruthiga
K
Mandelkow
Eva-Maria
EM
D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; C504812:SPRED1 protein, human; C097507:testis-specific protein kinase 1; D017346:Protein Serine-Threonine Kinases; C115483:TAO1 protein kinase; D020930:MAP Kinase Kinase Kinases