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APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function

Nature Cell Biology volume 8, pages 516–523 (2006)Cite this article

An Erratum to this article was published on 01 June 2006

Abstract

Adiponectin, also known as Acrp30, is an adipose tissue-derived hormone with anti-atherogenic, anti-diabetic and insulin sensitizing properties1,2,3. Two seven-transmembrane domain-containing proteins, AdipoR1 and AdipoR2, have recently been identified as adiponectin receptors4, 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.

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Figure 1: Identification of APPL1 as an AdipoR1 interacting protein.
Figure 2: The role of APPL1 in adiponectin signalling.
Figure 3: The role of APPL1 in glucose metabolism.
Figure 4: The role of Rab5 in the adiponectin signalling pathway.
Figure 5: The role of APPL1 in the cross talk between insulin signalling and adiponectin signalling.

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Acknowledgements

We thank M. A. Lim for generation of the APPL1 RNAi-suppressed cell lines, D. Hu and M, Chung for excellent technical assistance and V. Frohlich (Digital Optical Imaging Facility, UTHSCSA) for assistance with confocal microscopy studies. We also thank T. W. Wang for providing the yeast two-hybrid cDNA library, D. Accili for mouse hepatocyte cells, X. Y. Huang for wild-type and dominant negative (S34N) Rab5, J. H. Han for p38 MAPK constructs and M. J. Quon for the HA–GLUT4 and AMPK constructs. This work was supported in part by a Career Development Award from the American Diabetes Association (L.Q.D.) and National Institute of Health grants RO1 DK69930 (L.Q.D.), RO1 DK52933 (F.L.), pre-doctoral fellowship F31DK068874 (R.A.R.) and training grant T32 AG021890 (F.J.R. and J.Y.H.).

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Authors and Affiliations

  1. Department of Pharmacology, University of Texas Health Science Center, San Antonio, 78229–3900, TX, USA

    Xuming Mao, Lixin Wang, Fresnida J. Ramos, Qichen Fang, Christine Y. Christ-Roberts, Ryang-Yeo Kim, Feng Liu & Lily Q. Dong

  2. Department of Biochemistry, University of Texas Health Science Center, San Antonio, 78229–3900, TX, USA

    Chintan K. Kikani, Ramon A. Riojas, Paul Langlais & Feng Liu

  3. Departments of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, 78229–3900, TX, USA

    Jenny Y. Hong & Lily Q. Dong

  4. The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, 78229–3900, TX, USA

    Feng Liu & Lily Q. Dong

  5. Shanghai Diabetes Institute, Shanghai Jiaotong University Affiliated Sixth Hospital, Shanghai, 200233, People's Republic of China

    Qichen Fang

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Correspondence to Lily Q. Dong.

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Mao, X., Kikani, C., Riojas, R. et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol 8, 516–523 (2006). https://doi.org/10.1038/ncb1404

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