Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1.

The Journal of Biological Chemistry
Victoria Prieto-EchagüeW T Miller

Abstract

Ack1 is a nonreceptor tyrosine kinase that participates in tumorigenesis, cell survival, and migration. Relatively little is known about the mechanisms that regulate Ack1 activity. Recently, four somatic missense mutations of Ack1 were identified in cancer tissue samples, but the effects on Ack1 activity, and function have not been described. These mutations occur in the N-terminal region, the C-lobe of the kinase domain, and the SH3 domain. Here, we show that the cancer-associated mutations increase Ack1 autophosphorylation in mammalian cells without affecting localization and increase Ack1 activity in immune complex kinase assays. The cancer-associated mutations potentiate the ability of Ack1 to promote proliferation and migration, suggesting that point mutation is a mechanism for Ack1 deregulation. We propose that the C-terminal Mig6 homology region (MHR) (residues 802-990) participates in inhibitory intramolecular interactions. The isolated kinase domain of Ack1 interacts directly with the MHR, and the cancer-associated E346K mutation prevents binding. Likewise, mutation of a key hydrophobic residue in the MHR (Phe(820)) prevents the MHR-kinase interaction, activates Ack1, and increases cell migration. Thus, the cancer-asso...Continue Reading

References

Feb 13, 1997·Nature·F SicheriJ Kuriyan
Jul 18, 1997·The Journal of Biological Chemistry·S D BriggsT E Smithgall
Oct 6, 1997·The Journal of Biological Chemistry·W Yang, R A Cerione
Feb 5, 1999·Science·C D ThanosJ U Bowie
Mar 20, 1999·The Journal of Biological Chemistry·W YangR A Cerione
Aug 19, 2000·Molecular Cell·N A HopperP W Sternberg
Aug 31, 2000·Annual Review of Biochemistry·S R Hubbard, J H Till
Mar 30, 2001·The Journal of Biological Chemistry·W YangR A Cerione
May 18, 2001·Nature·P Blume-Jensen, T Hunter
Jun 8, 2001·Biochemical and Biophysical Research Communications·J Kato-StankiewiczT Satoh
Oct 18, 2001·The Journal of Cell Biology·X WuL E Greene
Feb 8, 2002·Cell·Helma PlukGiulio Superti-Furga
May 7, 2002·Nature Structural Biology·Chongwoo A KimJames U Bowie
May 23, 2002·Cell·Morgan Huse, John Kuriyan
Dec 10, 2002·Science·G ManningS Sudarsanam
Mar 26, 2003·Cell·Bhushan NagarJohn Kuriyan
Apr 13, 2005·Proceedings of the National Academy of Sciences of the United States of America·Mini ThomasAlexander M Klibanov
May 12, 2005·Molecular Cancer Research : MCR·Alam Nur-E-KamalWilliam J Welsh
Sep 3, 2005·FEBS Letters·Lee Yeow-FongEd Manser
Oct 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Edward Htun van der HorstScott Powers
Nov 1, 2005·The Journal of Biological Chemistry·Noriko YokoyamaW Todd Miller
Feb 14, 2006·Methods in Enzymology·Noriko Yokoyama, W Todd Miller
Jun 17, 2006·Proceedings of the National Academy of Sciences of the United States of America·Maria L GalisteoJoseph Schlessinger
Oct 14, 2006·The Journal of Biological Chemistry·Katarzyna ModzelewskaPatricia J Keely
Mar 9, 2007·Nature·Christopher GreenmanMichael R Stratton
May 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Nupam P MahajanYoung E Whang
Jun 19, 2007·Cell·Daniel LiethaMichael J Eck
Feb 12, 2008·Experimental Cell Research·Lene Melsaether GrøvdalEspen Stang

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Citations

Jun 4, 2011·Journal of Signal Transduction·Victoria Prieto-Echagüe, W Todd Miller
Oct 29, 2010·BMC Biochemistry·Victoria Prieto-EchagüeW Todd Miller
Apr 20, 2013·Cancer Letters·Kiran Mahajan, Nupam P Mahajan
Jan 23, 2014·Critical Reviews in Clinical Laboratory Sciences·Elzbieta GocekGeorge P Studzinski
Feb 12, 2011·The Biochemical Journal·Wing ChanEd Manser
Jul 9, 2016·BMC Biochemistry·M Zulema CabailW Todd Miller
May 26, 2017·The Journal of Biological Chemistry·George J N TetleyDarerca Owen
Mar 30, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xing-Hua XiaoLi-Xia Xiong
Oct 5, 2018·The Journal of Maternal-fetal & Neonatal Medicine : the Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians·Yangming LiuHongbo Qi
Nov 28, 2019·BioMed Research International·Xia LiuBaolin Han
May 5, 2012·The Biochemical Journal·Qiong LinWannian Yang
Jul 19, 2018·Science Signaling·Chelsea JenkinsJeffrey W Tyner
Nov 8, 2020·The Journal of Investigative Dermatology·Zhenyu JiHensin Tsao

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