Cell Signaling (Co-Leaders: Karen Reue and Susan Taylor)

The Cell Signaling Research Base comprises a multi-disciplinary group of accomplished faculty from each of the participating DRC Institutions. Investigators study insulin and growth factor action, kinases and phosphatases, G protein biology, vesicle trafficking, control of gene expression and other areas pertinent to diabetes and metabolism. Highlights include the following.


  1. Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4, by DRC members Montminy, Shaw, Rotter, Goodarzi, Chen and others in Cell Metabolism (2014). Montminy and colleagues show that leptin triggers catecholamine-dependent increases in cAMP signaling that reduce inflammatory gene expression via the activation of the histone deacetylase HDAC4. As variants in the HDAC4 gene are associated with obesity in humans, these results indicate that the cAMP-HDAC4 pathway functions importantly in maintaining insulin sensitivity and energy balance via its effects on the innate immune system.
  2. Differential regulation of mTORC1 by leucine and glutamine, by DRC member Guan and others in Science (2015). Guan and colleagues report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms. They identified the adenosine diphosphate ribosylation factor-1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine, uncovering a signaling cascade to mTORC1 activation.
  3. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress, by DRC member Shaw and others in Science (2015). Shaw and colleagues found that the energy-sensing AMP-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission and is a key effector of AMPK-mediated mitochondrial fission.
  4. TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue, by DRC
    members Saltiel and Reilly in Cell (2018). TBK1 is activated by pro-inflammatory cytokines, but its role in
    controlling metabolism remains unclear. Tbk1 expression is increased in adipocytes of HFD-fed mice.
    Adipocyte-specific TBK1 knockout attenuates obesity by increasing energy expenditure; further studies show
    that TBK1 directly inhibits AMPK to repress respiration and increase energy storage. Conversely, activation of AMPK under catabolic conditions can increase TBK1 activity through phosphorylation, mediated by AMPK's downstream target ULK1. TBK1 suppresses inflammation by phosphorylating and inducing the degradation of the IKK kinase NIK, thus attenuating NF-κB activity. Moreover, TBK1 mediates the negative impact of AMPK activity on NF-κB activation. These data implicate a unique role for TBK1 in mediating bidirectional crosstalk between energy sensing and inflammatory signaling pathways in both over- and undernutrition.