| Structural highlights
Function
[ULK3_HUMAN] Serine/threonine protein kinase that acts as a regulator of Sonic hedgehog (SHH) signaling and autophagy. Acts as a negative regulator of SHH signaling in the absence of SHH ligand: interacts with SUFU, thereby inactivating the protein kinase activity and preventing phosphorylation of GLI proteins (GLI1, GLI2 and/or GLI3). Positively regulates SHH signaling in the presence of SHH: dissociates from SUFU, autophosphorylates and mediates phosphorylation of GLI2, activating it and promoting its nuclear translocation. Phosphorylates in vitro GLI2, as well as GLI1 and GLI3, although less efficiently. Also acts as a regulator of autophagy: following cellular senescence, able to induce autophagy.[1] [2] [3] [IST1_HUMAN] Proposed to be involved in specific functions of the ESCRT machinery. Is required for efficient abscission during cytokinesis, but not for HIV-1 budding. The involvement in the MVB pathway is not established. Involved in recruiting VPS4A and/or VPS4B to the midbody of dividing cells.[4] [5]
Publication Abstract from PubMed
The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. Here we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains and thereby delays abscission in response to lagging chromosomes, nuclear pore defects and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1, an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations.
ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins.,Caballe A, Wenzel DM, Agromayor M, Alam SL, Skalicky JJ, Kloc M, Carlton JG, Labrador L, Sundquist WI, Martin-Serrano J Elife. 2015 May 26;4. doi: 10.7554/eLife.06547. PMID:26011858[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavare S, Arakawa S, Shimizu S, Watt FM, Narita M. Autophagy mediates the mitotic senescence transition. Genes Dev. 2009 Apr 1;23(7):798-803. doi: 10.1101/gad.519709. Epub 2009 Mar 11. PMID:19279323 doi:http://dx.doi.org/10.1101/gad.519709
- ↑ Maloverjan A, Piirsoo M, Michelson P, Kogerman P, Osterlund T. Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway. Exp Cell Res. 2010 Feb 15;316(4):627-37. doi: 10.1016/j.yexcr.2009.10.018. Epub, 2009 Oct 21. PMID:19878745 doi:http://dx.doi.org/10.1016/j.yexcr.2009.10.018
- ↑ Maloverjan A, Piirsoo M, Kasak L, Peil L, Osterlund T, Kogerman P. Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway. J Biol Chem. 2010 Sep 24;285(39):30079-90. doi: 10.1074/jbc.M110.133991. Epub, 2010 Jul 19. PMID:20643644 doi:http://dx.doi.org/10.1074/jbc.M110.133991
- ↑ Bajorek M, Morita E, Skalicky JJ, Morham SG, Babst M, Sundquist WI. Biochemical analyses of human IST1 and its function in cytokinesis. Mol Biol Cell. 2009 Mar;20(5):1360-73. doi: 10.1091/mbc.E08-05-0475. Epub 2009, Jan 7. PMID:19129479 doi:http://dx.doi.org/10.1091/mbc.E08-05-0475
- ↑ Agromayor M, Carlton JG, Phelan JP, Matthews DR, Carlin LM, Ameer-Beg S, Bowers K, Martin-Serrano J. Essential role of hIST1 in cytokinesis. Mol Biol Cell. 2009 Mar;20(5):1374-87. doi: 10.1091/mbc.E08-05-0474. Epub 2009, Jan 7. PMID:19129480 doi:http://dx.doi.org/10.1091/mbc.E08-05-0474
- ↑ Caballe A, Wenzel DM, Agromayor M, Alam SL, Skalicky JJ, Kloc M, Carlton JG, Labrador L, Sundquist WI, Martin-Serrano J. ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins. Elife. 2015 May 26;4. doi: 10.7554/eLife.06547. PMID:26011858 doi:http://dx.doi.org/10.7554/eLife.06547
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