APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function

Abstract

Adiponectin, also known as Acrp30, is an adipose tissue-derived hormone with anti-atherogenic, anti-diabetic and insulin sensitizing properties. Two seven-transmembrane domain-containing proteins, AdipoR1 and AdipoR2, have recently been identified as adiponectin receptors, yet signalling events downstream of these receptors remain poorly defined. By using the cytoplasmic domain of AdipoR1 as bait, we screened a yeast two-hybrid cDNA library derived from human fetal brain. This screening led to the identification of a phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding (PTB) domain and leucine zipper motif). APPL1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. Overexpression of APPL1 increases, and suppression of APPL1 level reduces, adiponectin signalling and adiponectin-mediated downstream events (such as lipid oxidation, glucose uptake and the membrane translocation of glucose transport 4 (GLUT4)). Adiponectin stimulates the interaction between APPL1 and Rab5 (a small GTPase) interaction, leading to increased GLUT4 membrane translocation. APPL1 also acts as a critical regulator of the crosstalk between adiponectin signalling and insulin signalling pathways. These results demonstrate a key function for APPL1 in adiponectin signalling and provide a molecular mechanism for the insulin sensitizing function of adiponectin.

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

“…Indeed, it has been shown that the insulin signaling pathway is regulated by various feedback mechanisms. For instance, plasma insulin is upregulated in response to downregulation of insulin receptor signaling, resulting in insulin resistance,46 and APPL1, an adaptor protein containing a PH domain, PTB domain, and leucine zipper motif,47 has been increased in AD, perhaps in response to impaired insulin receptor signaling 48…”

The ‘beneficial’ adipokines in reproduction and fertility

“…27 These receptors are biologically active, as they bind to a protein known as adaptor protein-containing pleckstrin homology domain, phosphotyrosine-binding domain and leucine zipper motif (APPL1), and provoke intracellular signaling. 28,29 Circulating adiponectin concentrations correlate negatively with body fat in mammals. 30 The concentration of adiponectin in circulation can exceed 10 mg ml À1 in humans and is inversely related to adipose mass.…”

“…34 There is evidence for adiponectin activation of the peripheral peroxisome-activated receptor-g in placental tissue 57 and mitogen-activated protein kinase pathways in vascular tissue 70,71 and osteoblasts. 72 The recent discovery of interactions between the AdipoR1 and R2 and the adapter protein APPL1 28,29 has provided new insight into the mechanism by which adiponectin can act on target tissues. APPL1 has been implicated in the regulation of cross-talk between the insulin and adiponectin transduction pathways.…”

“…APPL1 has been implicated in the regulation of cross-talk between the insulin and adiponectin transduction pathways. 28 In addition, the interaction of APPL1 with epidermal growth factor induces translocation of the linker protein to the nucleus, where it associates with a chromatin-remodeling complex that regulates transcription. 73 It is reasonable that interactions of APPL1 with adiponectin, FSH and insulin receptors may precipitate a similar signaling process, although no data yet exist to confirm this assumption.…”

“…76 In the context of interaction with insulin, small interfering RNA (siRNA) knockdown of APPL1 expression interferes with insulin induction of Akt/PKB in muscle cells. 28 Although direct confirmation is lacking, it may be that APPL1 interacts directly with the insulin receptor. Further clarification is required, with emphasis on the understanding of hormone/ adiponectin interactions in the ovary.…”