Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways.
Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways.
Department of Infection, Immunity &Cardiovascular Disease, University of Sheffield, Beech Hill road, Sheffield, S10 2RX, United Kingdom.
Hongtao
H
Guan
Department of Infection, Immunity &Cardiovascular Disease, University of Sheffield, Beech Hill road, Sheffield, S10 2RX, United Kingdom.
Aban
A
Shuaib
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
David Davila De
DD
Leon
Department of Infection, Immunity &Cardiovascular Disease, University of Sheffield, Beech Hill road, Sheffield, S10 2RX, United Kingdom.
Adrienn
A
Angyal
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
Maria
M
Salazar
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.|Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
Guillermo
G
Velasco
Department of Computer Science, University of Sheffield, Beech Hill road, Sheffield, S10 2RX, United Kingdom.
Mike
M
Holcombe
Department of Infection, Immunity &Cardiovascular Disease, University of Sheffield, Beech Hill road, Sheffield, S10 2RX, United Kingdom.|Bio21 Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria, 3010, Australia.|CSL Limited, 45 Poplar Rd, Parkville, Victoria 3052, Australia.
Steven K
SK
Dower
Department of Infection, Immunity &Cardiovascular Disease, University of Sheffield, Beech Hill road, Sheffield, S10 2RX, United Kingdom.
Endre
E
Kiss-Toth
D000818:Animals; D001667:Binding, Competitive; D020536:Enzyme Activators / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000201:enzymology
D020536:Enzyme Activators; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases