Dynamic interplay between nitration and phosphorylation of tubulin cofactor B in the control of microtubule dynamics.
Tubulin cofactor B (TCoB) plays an important role in microtubule dynamics by facilitating the dimerization of alpha- and beta-tubulin. Recent evidence suggests that p21-activated kinase 1 (Pak1), a major signaling nodule in eukaryotic cells, phosphorylates TCoB on Ser-65 and Ser-128 and plays an essential role in microtubule regrowth. However, to date, no upstream signaling molecules have been identified to antagonize the functions of TCoB, which might help in maintaining the equilibrium of microtubules. Here, we discovered that TCoB is efficiently nitrated, mainly on Tyr-64 and Tyr-98, and nitrated-TCoB attenuates the synthesis of new microtubules. In addition, we found that nitration of TCoB antagonizes signaling-dependent phosphorylation of TCoB, whereas optimal nitration of TCoB requires the presence of functional Pak1 phosphorylation sites, thus providing a feedback mechanism to regulate phosphorylation-dependent MT regrowth. Together these findings identified TCoB as the third cytoskeleton protein to be nitrated and suggest a previously undescribed mechanism, whereby growth factor signaling may coordinately integrate nitric oxide signaling in the regulation of microtubule dynamics.
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Suresh K
SK
Rayala
Emil
E
Martin
Iraida G
IG
Sharina
Poonam R
PR
Molli
Xiaoping
X
Wang
Raymond
R
Jacobson
Ferid
F
Murad
Rakesh
R
Kumar
D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D018832:Molecular Chaperones; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism; D010766:Phosphorylation; D014443:Tyrosine / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; C501073:tubulin cofactor B, human; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D054462:p21-Activated Kinases; D009584:Nitrogen