Protein interacting with Amyloid Precursor Protein tail-1 (PAT1) is involved in early endocytosis
Protein interacting with Amyloid Precursor Protein (APP) tail 1 (PAT1) also called APPBP2 or Ara 67 has different targets such as APP or androgen receptor and is expressed in several tissues. PAT1 is known to be involved in the subcellular trafficking of its targets. We previously observed in primary neurons that PAT1 is poorly associated with APP at the cell surface. Here we show that PAT1 colocalizes with vesicles close to the cell surface labeled with Rab5, Rab4, EEA1 and Rabaptin-5 but not with Rab11 and Rab7. Moreover, PAT1 expression regulates the number of EEA1 and Rab5 vesicles, and endocytosis/recycling of the transferrin receptor. In addition, low levels of PAT1 decrease the size of transferrin-colocalized EEA1 vesicles with time following transferrin uptake. Finally, overexpression of the APP binding domain to PAT1 is sufficient to compromise endocytosis. Altogether, these data suggest that PAT1 is a new actor in transferrin early endocytosis. Whether this new function of PAT1 may have consequences in pathology remains to be determined.
KeywordsPAT1 Neuron Endocytosis Transferrin uptake Caspase cleaved APP
We thank Dr. Sanjay W. Pimplikar for mab26 to PAT1 and Dr. Marino Zerial for Rabaptin-5 antibody and Dr. Christophe Lamaze for helpful discussions. This work was supported by Institut National de la Santé et de la Recherche Médicale, France and by Fondation Jérôme Lejeune, France.
Compliance with ethical standards
Conflict of interest
There are no actual or potential conflicts of interests between the authors and this work.
- 4.Hirasawa A, Saito-Ohara F, Inoue J, Aoki D, Susumu N, Yokoyama T, Nozawa S, Inazawa J, Imoto I (2003) Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Clin Cancer Res 9:1995–2004PubMedGoogle Scholar
- 6.Ehrbrecht A, Muller U, Wolter M, Hoischen A, Koch A, Radlwimmer B, Actor B, Mincheva A, Pietsch T, Lichter P, Reifenberger G, Weber RG (2006) Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J Pathol 208:554–563PubMedGoogle Scholar
- 8.Hsu CL, Chen YL, Ting HJ, Lin WJ, Yang Z, Zhang Y, Wang L, Wu CT, Chang HC, Yeh S, Pimplikar SW, Chang C (2005) Androgen Receptor (AR) NH2-and CooH-Terminal interactions result in the differential influences on the AR-mediated transactivation and cell growth. Mol Endocrinol 19:350–361PubMedGoogle Scholar
- 15.McClelland A, Kükn LC, Ruddle FH (1984) The human transferrin receptor gene: genomic organization, and the complete primary structure of the receptor deduced from a cDNA sequence. Cell 30:267–274Google Scholar
- 20.Serra J (1982) Image analysis and mathematical morphology, vol 1. Academic Press, London, pp 1–610Google Scholar
- 21.Mu FT, Callaghan JM, Steele-Mortimer O, Stenmark H, Parton RG, Campbell PL, McCluskey J, Yeo JP, Tock EP, Toh BH (1995) EEA1, an early endosome-associated protein. EEA1 is a conserved alpha-helical peripheral membrane protein flanked by cysteine “fingers” and contains a calmodulin-binding IQ motif. J Biol Chem 270:13503–13511PubMedGoogle Scholar
- 32.Facchinetti P, Dorard E, Contremoulins V, Gaillard MC, Deglon N, Sazdovitch V, Guihenneuc-Jouyaux C, Brouillet E, Duyckaerts C, Allinquant B (2014) SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients. Neurobiol Aging 35:958–968PubMedGoogle Scholar
- 37.Grady EF, Gamp PD, Jones E, Baluk P, McDonald DM, Payan DG, Bunnett NW (1996) Endocytosis and recycling of neurokinin 1 receptors in enteric neurons. Neuroscience 79:1239–1254Google Scholar
- 40.Zeigerer A, Gilleron J, Bogorad RL, Marsico G, Nonaka H, Seifert S, Epstein-Barash H, Kuchimanchi S, Peng CG, Ruda VM, del Conte-Zerial P, Hengstler JG, Kalaidzikis Y, Koteliansky V, Zerial M (2012) Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature 485:465–470PubMedGoogle Scholar
- 47.Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA (2000) Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol 157:277–286PubMedPubMedCentralGoogle Scholar
- 48.Cataldo AM, Mathews PM, Boiteau AB, Hassinger LC, Peterhoff CM, Jiang Y, Mullaney K, Neve RL, Gruenberg J, Nixon RA (2008) Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects. Am J Pathol 173:370–384PubMedPubMedCentralGoogle Scholar
- 50.Cossec JC, Lavaur J, Berman DE, Rivals I, Hoischen A, Stora S, Ripoll C, Mircher C, Gratteau Y, OlivoMarin JC, de Chaumont F, Lecourtois M, Antonarakis SE, Veltman JA, Delabar JM, Duyckaerts C, di Paolo G, Potier MC (2012) Trisomy for synaptojanin1 in down syndrome is functionally linked to the enlargement of early endosomes. Hum Mol Genet 21:3156–3172PubMedPubMedCentralGoogle Scholar