APPL1 explained

Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), or DCC-interacting protein 13-alpha (DIP13alpha), is a protein that in humans is encoded by the APPL1 gene.^{[1] [2] [3]} APPL1 contains several key interactory domains: pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain and Bin–Amphiphysin–Rvs (BAR) domain.^[4]

Function

APPL1 is an adaptor protein localized to a subset of Rab5-positive ("early") endosomes, where it recruits other binding partners and regulates vesicle trafficking and endosomal signalling. APPL1 is enriched at very early endosomes which are negative for EEA1, indicating that APPL1 affects the earliest stages of endosomal traffic before EEA1 takes over. This is in line with observations that APPL1 and EEA1 compete for Rab5 binding. APPL1 affects the speed of internalization of key endosomal cargo (eg. EGF receptor) which is dependent on Rab5 activation.

PTB domain of APPL1 regulates many cell signalling events in specific endosomal compartments - sometimes termed the "signalling endosomes". This includes lysophosphatidic acid (LPA)-induced signaling (together with interacting protein GIPC1). Additional roles for APPL1 were pinpointed to the nucleus where APPL1 can localize once dissociated from endosomes.

Mutant studies

Mouse Mutant Alleles for Appl1
Marker Symbol for Mouse Gene. This symbol is assigned to the genomic locus by the MGI	Appl1
Mutant Mouse Embryonic Stem Cell Clones. These are the known targeted mutations for this gene in a mouse.	Appl1^tm1a(KOMP)Wtsi
Example structure of targeted conditional mutant allele for this gene
These Mutant ES Cells can be studied directly or used to generate mice with this gene knocked out. Study of these mice can shed light on the function of Appl1:see Knockout mouse

Interactions

APPL1 has been shown to interact with Deleted in Colorectal Cancer,^[5] AKT2, but also Rab5, Rab21, OCRL and almost 30 other proteins.

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T . Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones . DNA Research . 9 . 3 . 99–106 . June 2002 . 12168954 . 10.1093/dnares/9.3.99 . free .
• Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O . Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 7 . 1 . 65–73 . February 2000 . 10718198 . 10.1093/dnares/7.1.65 . free .
• Liu J, Yao F, Wu R, Morgan M, Thorburn A, Finley RL, Chen YQ . Mediation of the DCC apoptotic signal by DIP13 alpha . The Journal of Biological Chemistry . 277 . 29 . 26281–5 . July 2002 . 12011067 . 10.1074/jbc.M204679200 . free .
• Yang L, Lin HK, Altuwaijri S, Xie S, Wang L, Chang C . APPL suppresses androgen receptor transactivation via potentiating Akt activity . The Journal of Biological Chemistry . 278 . 19 . 16820–7 . May 2003 . 12621049 . 10.1074/jbc.M213163200 . free .
• Miaczynska M, Christoforidis S, Giner A, Shevchenko A, Uttenweiler-Joseph S, Habermann B, Wilm M, Parton RG, Zerial M . APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment . Cell . 116 . 3 . 445–56 . February 2004 . 15016378 . 10.1016/S0092-8674(04)00117-5 . 18281503 . free .
• Nechamen CA, Thomas RM, Cohen BD, Acevedo G, Poulikakos PI, Testa JR, Dias JA . Human follicle-stimulating hormone (FSH) receptor interacts with the adaptor protein APPL1 in HEK 293 cells: potential involvement of the PI3K pathway in FSH signaling . Biology of Reproduction . 71 . 2 . 629–36 . August 2004 . 15070827 . 10.1095/biolreprod.103.025833 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . August 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Ballif BA, Villén J, Beausoleil SA, Schwartz D, Gygi SP . Phosphoproteomic analysis of the developing mouse brain . Molecular & Cellular Proteomics . 3 . 11 . 1093–101 . November 2004 . 15345747 . 10.1074/mcp.M400085-MCP200 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, Fang Q, Christ-Roberts CY, Hong JY, Kim RY, Liu F, Dong LQ . APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function . Nature Cell Biology . 8 . 5 . 516–23 . May 2006 . 16622416 . 10.1038/ncb1404 . 21273764 .
• Li J, Mao X, Dong LQ, Liu F, Tong L . Crystal structures of the BAR-PH and PTB domains of human APPL1 . Structure . 15 . 5 . 525–33 . May 2007 . 17502098 . 10.1016/j.str.2007.03.011 . free .
• Zhu G, Chen J, Liu J, Brunzelle JS, Huang B, Wakeham N, Terzyan S, Li X, Rao Z, Li G, Zhang XC . Structure of the APPL1 BAR-PH domain and characterization of its interaction with Rab5 . The EMBO Journal . 26 . 14 . 3484–93 . July 2007 . 17581628 . 1933402 . 10.1038/sj.emboj.7601771 .
• Saito T, Jones CC, Huang S, Czech MP, Pilch PF . The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation . The Journal of Biological Chemistry . 282 . 44 . 32280–7 . November 2007 . 17848569 . 10.1074/jbc.M704150200 . free .

Notes and References

1. Mitsuuchi Y, Johnson SW, Sonoda G, Tanno S, Golemis EA, Testa JR . Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2 . Oncogene . 18 . 35 . 4891–8 . September 1999 . 10490823 . 10.1038/sj.onc.1203080 . 25245749 .
2. Nechamen CA, Thomas RM, Dias JA . APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex . Molecular and Cellular Endocrinology . 260-262 . 93–9 . January 2007 . 17030088 . 1782224 . 10.1016/j.mce.2006.08.014 .
3. Web site: Entrez Gene: APPL1 adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1.
4. Diggins NL, Webb DJ . APPL1 is a multifunctional endosomal signaling adaptor protein . en . Biochemical Society Transactions . 45 . 3 . 771–779 . June 2017 . 28620038 . 10.1042/bst20160191 . 5844352 .
5. Liu J, Yao F, Wu R, Morgan M, Thorburn A, Finley RL, Chen YQ . Mediation of the DCC apoptotic signal by DIP13 alpha . The Journal of Biological Chemistry . 277 . 29 . 26281–5 . July 2002 . 12011067 . 10.1074/jbc.M204679200 . free .