APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

Abstract

Xin X, Zhou L, Reyes CM, Liu F, Dong LQ. APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. Am J Physiol Endocrinol Metab 300: E103-E110, 2011. First published October 26, 2010 doi:10.1152/ajpendo.00427.2010.-The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-␤-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectinstimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNF␣-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.APPL1; transforming growth factor-␤-activated kinase 1; mitogenactivated protein kinase kinase 3; p38 mitogen-activated protein kinase ADIPONECTIN IS AN ADIPOSE-derived hormone that plays an important role in the regulation of energy homeostasis (2, 10, 28). The binding of adiponectin to its membrane receptors, such as AdipoR1 and AdipoR2, leads to the activation of two major signal pathways in muscle cells, the AMP-activated protein kinase (AMPK) and the p38 mitogen-activated protein kinase (MAPK) pathways (16,27). Activation of these pathways has been shown to be essential for adiponectin-induced glucose uptake and fatty acid oxidation (16,27,28). APPL1 (adaptor protein containing PH domain, PTB domain and leucine zipper motif-1) is an adaptor protein containing multiple protein-protein interaction domains and was originally reported as an associating protein that interacts with the catalytic subunit of phosphatidylinositol 3-kinase (p110) and Akt (17). Our laboratory has recently shown that APPL1 mediates adiponectin signaling to activate both the AMPK and the p38 MAPK signaling pathways (7,16,29). However, despite the finding that APPL1 mediates adiponectin-stimulated AMPK activation by promoting the cytosolic translocation of AMPK upstream kinase LKB1 (29), the molecular mechanism underlying APPL1-regulated p38 MAPK activation remains elusive.The p38 MAPK is a major kinase in the MAPK family and plays essential roles in regulating cell proliferation, inflammation, and immune responses (19). Recent studies suggest that p38 MAPK acts as an essential mediator in regulating adiponectin-induced glucose uptake and fatty acid oxidation...

Adipose tissue in control of metabolism

“…There is accumulating evidence showing that adiponectin exhibits insulin sensitizing effect through multiple signalling pathways downstream of adiponectin receptors, such as AMPK, Ca 2+ , PPARα, ceramide and S1P 231:3 , Zhou et al 2009, Iwabu et al 2010, Holland et al 2011. Moreover, as an AdipoR1 and AdipoR2 interactive protein, APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine-binding domain and leucine zipper motif) positively mediates adiponectin signalling and its insulin sensitizing effect in muscle cells (Mao et al 2006, Zhou et al 2009, Fang et al 2010, Cleasby et al 2011, Xin et al 2011. AMPK pathway, downstream of adiponectin receptor signalling, is critical for adiponectin action in the liver, muscle and other organs (Yamauchi et al 2002).…”

Globular adiponectin induces LKB1/AMPK-dependent glucose uptake via actin cytoskeleton remodeling

“…Indeed, the regulation of glucose transport by adiponectin in skeletal muscle is dependent on the interaction of APPL1 with AdipoR (Mao et al 2006, 2009a, Zhou et al 2009, Xin et al 2011, leading to the subsequent activation of AMPK (Tomas et al 2002, Yamauchi et al 2002, Tsao et al 2003, Ceddia et al 2005, Mao et al 2006, Zhou et al 2009). Adiponectin-induced phosphorylation and activation of AMPK are primarily mediated through the cytosolic translocation of LKB1, which is mediated by PKC-z (Deepa et al 2011), and the interaction of LKB1 with APPL1, which localizes it to the cytosol (Zhou et al 2009, Fang et al 2010.…”

“…It is apparent that many of the favorable metabolic effects of adiponectin are mediated via AMPK-dependent signaling (Yamauchi & Kadowaki 2008, Matsuzawa 2010. Recent studies have also established that binding of ligands to adiponectin receptors (AdipoRs) leads to the recruitment of APPL1-and PKC-z-dependent nuclear export of LKB1 resulting in the activation of AMPK (Mao et al 2006, Zhou et al 2009, Fang et al 2010, Xin et al 2011.…”

Information Thermodynamics Derives the Entropy Current of Cell Signal Transduction as a Model of a Binary Coding System

“…Further, using the diffusion coefficient of an active signaling molecule, the average entropy current per signal duration is given using the diffusion coefficient of the signal, D j and from (22):…”

“…External stimulation on the cell induces a concentration fluctuation in the phosphorylation of the signaling molecules. More specifically, a fluctuation in the signaling molecules' concentration tentatively increases, followed by a decrease over a long duration, τ j , of several hours [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] (Figure 1). Here, we defined the occurrence probability, p j and p j * , which represents the selection probability of j-th step using X j or X j *, respectively:…”