Human Tribbles-1 Controls Proliferation and Chemotaxis of Smooth Muscle Cells via MAPK Signaling Pathways

Abstract

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 mitogenactivated 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.

Abnormal expression of TRIB3 in colorectal cancer: a novel marker for prognosis

“…Trib1 interacts with Mapk and modulates Mapkk activity associated with smooth muscle cell proliferation and migration (Kiss-Toth et al, 2004;Sung et al, 2007). Trib2 has a role in adipogenesis in combination with the degradation of C/EBPbeta (Naiki et al, 2007).…”

Developmental roles of tribbles protein family members

“…In a similar manner, mammalian Tribs appear to regulate differentiation linked to cell division during (1) hematopoiesis (Lin et al, 2007;Eder et al, 2008;Sathyanarayana et al, 2008), (2) myogenesis (Kato and Du, 2007;Sung et al, 2007), (3) vascular smooth muscle formation (Chan et al, 2010), (4) lymphocyte differentiation (Selim et al, 2007), and (5) adipogenesis (described below).…”

“…Because Trib3 is induced in tumors experiencing stress/ starvation conditions, it may contribute to the ability of cells to grow under the nutrient limiting conditions typical within a tumor (Bowers et al, 2003;Schwarzer et al, 2006). In atherosclerotic arteries, Trib1 controls smooth muscle cell proliferation by regulating Jnk kinase signaling (Sung et al, 2007).…”

TRIB1 (tribbles pseudokinase 1)

“…TRIB1 also interacts with MKK4, a JNK activator and implicated in the migration and proliferation of smooth muscle and involved in the pathogenesis of atherosclerosis. The nuclear localisation of TRIB1-MKK4 complex is dependent on the NT domain of TRIB1, however the central kinase-like domain of TRIB1 is sufficient for its interaction with MKK4 but the interaction is no longer preferentially nuclear (Sung, et al 2007). COP1 AND C/EBPalpha TRIB1 contains a COP1 binding site at the carboxy terminus.…”

“…TRIB1 is selectively over-expressed in chronically inflamed human atherosclerotic arteries and regulates vascular smooth muscle cell (VSMC) chemotaxis and proliferation, a characteristic feature of atherosclerosis via the JNK pathway (Sung, et al 2007). …”