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.[5][6][7] APPL1 contains several key interactory domains: pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain and Bin–Amphiphysin–Rvs (BAR) domain.[8]

APPL1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesAPPL1, APPL, DIP13alpha, MODY14, adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1
External IDsOMIM: 604299; MGI: 1920243; HomoloGene: 32143; GeneCards: APPL1; OMA:APPL1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_012096

NM_145221

RefSeq (protein)

NP_036228

NP_660256

Location (UCSC)Chr 3: 57.23 – 57.28 MbChr 14: 26.64 – 26.69 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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.[8]

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.[8]

Mutant studies

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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. Appl1tm1a(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

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APPL1 has been shown to interact with Deleted in Colorectal Cancer,[9] AKT2,[5] but also Rab5, Rab21, OCRL and almost 30 other proteins.[8]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000157500Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040760Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Mitsuuchi Y, Johnson SW, Sonoda G, Tanno S, Golemis EA, Testa JR (September 1999). "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. doi:10.1038/sj.onc.1203080. PMID 10490823. S2CID 25245749.
  6. ^ Nechamen CA, Thomas RM, Dias JA (January 2007). "APPL1, APPL2, Akt2 and FOXO1a interact with FSHR in a potential signaling complex". Molecular and Cellular Endocrinology. 260–262: 93–9. doi:10.1016/j.mce.2006.08.014. PMC 1782224. PMID 17030088.
  7. ^ "Entrez Gene: APPL1 adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1".
  8. ^ a b c d Diggins NL, Webb DJ (June 2017). "APPL1 is a multifunctional endosomal signaling adaptor protein". Biochemical Society Transactions. 45 (3): 771–779. doi:10.1042/bst20160191. PMC 5844352. PMID 28620038.
  9. ^ Liu J, Yao F, Wu R, Morgan M, Thorburn A, Finley RL, Chen YQ (July 2002). "Mediation of the DCC apoptotic signal by DIP13 alpha". The Journal of Biological Chemistry. 277 (29): 26281–5. doi:10.1074/jbc.M204679200. PMID 12011067.

Further reading

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