Mnk1 Is Required for Angiotensin II–Induced Protein Synthesis in Vascular Smooth Muscle Cells

Abstract

Abstract-Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. (VSMCs) and may contribute to pathological states associated with atherosclerosis, hypertension, and balloon injury. However, the molecular mechanisms involved in Ang II-induced hypertrophy remain largely unknown. In general, changes in protein synthesis results from alterations at the transcriptional and translational levels. The global nature of trophic stimulation by Ang II suggests that alterations in translation-initiation of preexisting mRNA may be involved.Initiation of mRNA translation is controlled by multiple protein-protein interactions and phosphorylation/dephosphorylation mechanisms. Eukaryotic initiation factor 4E (eIF4E) plays a key role in mRNA translation and its regulation. 1,2 eIF4E binds to the 7-methylguanosine triphosphate ("cap") structure at the 5Ј-end of cytoplasmic mRNA and interacts with eIF4G, a large scaffold protein that binds to other translation factors, including eIF4A and eIF3. This complex of eIF4E, eIF4G, and eIF4A is termed eIF4F, and functions to translocate mRNA to the proper position, thereby promoting translation. 3 Phosphorylation of eIF4E increases its affinity for the 5Ј-cap 4 and facilitates its incorporation into eIF4F complexes. 1 Indeed, stimulators of translation often result in enhanced phosphorylation of eIF4E.A new substrate for extracellular signal-regulated kinase (ERK), called mitogen-activated protein (MAP) kinase signal-integrating kinase-1 (Mnk1), was recently discovered. Mnk1 is a serine/threonine kinase that phosphorylates eIF4E in vitro. 5,6 Studies using dominant-negative or activated Mnk1 mutants demonstrated that TPA-induced activation of Mnk1 resulted in direct modulation of eIF4E phosphorylation. Further, activation of Mnk1 by anisomycin, UV, TNF-␣, or IL-1␤ was mediated by p38 MAPK, whereas TPA-induced Mnk1-activation was mediated via ERK. Interestingly, activation of Mnk1 by serum was mediated by both ERK and p38 MAPK. 7

Angiotensin II-Induced Osteopontin Expression in Vascular Smooth Muscle Cells Involves Gq/11, Ras, ERK, Src and Ets-1

“…We previously demonstrated that Ras is required for activation of Mnk1/2, which are kinases that are downstream of extracellular signal-regulated kinase (ERK) (22). To determine the role of ERK1/2 and other MAP kinase family members in Ang II-induced OPN expression, pharmacological inhibitors and kinase-inactive mutants of MEK1 (the kinase immediately upstream kinase of ERK), JNK, and p38MAPK were used.…”

β-Arrestin-mediated Signaling Regulates Protein Synthesis

“…In reviewing the literature on such cytosolic substrates of ERK1/2, we found a number of proteins involved in the modulation of protein synthesis, including MAP kinase-interacting kinase 1 (Mnk1). Because Mnk1 can be activated by a 7TMR (11), the angiotensin II receptor, we reasoned it might well be a ␤-arrestin ERK1/2 substrate and that ␤-arrestins might be involved in signaling to protein synthesis.…”

“…Using rat vascular smooth muscle cells, Ishida et al (19) measured the protein synthetic response to angiotensin II (AngII) (11). By using a chemical inhibitor of Mnk1 kinase activity, the authors found that Mnk1 activity was absolutely required for AngII stimulation of protein synthesis.…”

Mnk1 (Mitogen-Activated Protein Kinase–Interacting Kinase 1) Deficiency Aggravates Cardiac Remodeling in Mice

“…In vascular smooth muscle cells, the activation of Mnk1/eIF4E pathway contributes to Ang II-induced protein synthesis and hypertrophy. 35 One recent research demonstrated that Mnk inhibitor CGP57380 affected translation of only those mRNAs that contain both a cap and a hairpin in the 5′-untranslated regions. 36 Mnk1 may affect translation of specific mRNAs in different cells.…”