Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways.
Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall. Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen-activated protein kinase (MAPK) activation, although the molecular mechanisms of this process are poorly understood. Here we report that tribbles-1, a recently described modulator of MAPK activation, controls vascular smooth muscle cell proliferation and chemotaxis via the Jun kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The activity of this kinase is dependent on tribbles-1 levels, whereas the activation and the expression of MKK4/SEK1 are not. In addition, tribbles-1 expression is elevated in human atherosclerotic arteries when compared with non-atherosclerotic controls, suggesting that this protein may play a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology.
Sung
Hye Youn
HY
Cardiovascular Research Unit, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Guan
Hongtao
H
Section of Infection, Inflammation and Immunity, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Czibula
Agnes
A
Institute of Genetics, Biological Research Centre, H-6701 Szeged, Hungary.
King
Andrea R
AR
Cardiovascular Research Unit, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Eder
Katalin
K
Institute of Biochemistry, Biological Research Centre, H-6701 Szeged, Hungary.
Heath
Emily
E
Cardiovascular Research Unit, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Suvarna
S Kim
SK
Department of Histopathology, Northern General Hospital, Sheffield S5 7AU, United Kingdom.
Dower
Steven K
SK
Section of Infection, Inflammation and Immunity, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Wilson
Anthony G
AG
Section of Infection, Inflammation and Immunity, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Francis
Sheila E
SE
Cardiovascular Research Unit, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Crossman
David C
DC
Cardiovascular Research Unit, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Kiss-Toth
Endre
E
Cardiovascular Research Unit, University of Sheffield, Sheffield S10 2TN, United Kingdom. Electronic address: E.Kiss-Toth@sheffield.ac.uk.
D050197:Atherosclerosis; D001706:Biopsy; D002465:Cell Movement; D049109:Cell Proliferation; D002633:Chemotaxis; D006801:Humans; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology* / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D015854:Up-Regulation; D014945:Wound Healing
D047908:Intracellular Signaling Peptides and Proteins; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases