The small leucine-rich proteoglycan decorin interacts with the epidermal growth factor receptor (EGFR) and triggers a signaling cascade that leads to elevation of endogenous p21 and growth suppression. We demonstrate that decorin causes a sustained down-regulation of the EGFR. Upon stable expression of decorin, the EGFR number is reduced by ϳ40%, without changes in EGFR expression. However, EGFR phosphorylation is nearly completely abolished. Concurrently, decorin attenuates the EGFR-mediated mobilization of intracellular calcium and blocks the growth of tumor xenografts by down-regulating the EGFR kinase in vivo. Thus, decorin acts as an autocrine and paracrine regulator of tumor growth and could be utilized as an effective anticancer agent.
After a meal, insulin suppresses lipolysis through the activation of its downstream kinase, Akt, resulting in the inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin resistance, this process is ineffective, leading to a characteristic dyslipidemia and the worsening of impaired insulin action and obesity. Here, we describe a noncanonical Akt-independent, phosphoinositide-3 kinase (PI3K)-dependent pathway that regulates adipocyte lipolysis using restricted subcellular signaling. This pathway selectively alters the PKA phosphorylation of its major lipid droplet-associated substrate, perilipin. In contrast, the phosphorylation of another PKA substrate, hormone-sensitive lipase (HSL), remains Akt dependent. Furthermore, insulin regulates total PKA activity in an Akt-dependent manner. These findings indicate that localized changes in insulin action are responsible for the differential phosphorylation of PKA substrates. Thus, we identify a pathway by which insulin regulates lipolysis through the spatially compartmentalized modulation of PKA.
Forkhead box O (FOXO) transcription factors play an important role in modulating metabolic functions. FOXO is regulated by several modifications, but one of the most critical is phosphorylation and nuclear exclusion by Akt. Given the impact of insulin signaling on Akt-mediated phosphorylation of FOXO and the relatively high expression of Foxo1 in insulin-responsive tissues, this transcription factor is highly poised to regulate energy metabolism. When nutrient and insulin levels are low, Foxo1 promotes expression of gluconeogenic enzymes. Conversely, in the fed state, insulin levels rise and stimulate uptake of glucose primarily into skeletal muscle and other organs, including adipose tissue. Under certain pathophysiologic conditions, including insulin resistance, negative signaling to Foxo1 is compromised. Further clarification of the role of Foxo1 in insulin-responsive tissues will strengthen our understanding and allow us to better combat insulin resistance and diabetes mellitus.
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