Alternative titles; symbols
HGNC Approved Gene Symbol: APPL2
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38) : 12:105,173,300-105,236,174 (from NCBI)
Bonaglia et al. (2001) stated that the FLJ10659 gene encodes a 541-amino acid protein. Northern blot analysis detected a 4-kb transcript in several tissues, including kidney, brain, heart, and skeletal muscle. The FLJ10659 transcript was expressed in all central nervous system samples.
By affinity chromatography and mass spectrometry to identify RAB5 (179512) interactors, followed by RT-PCR using HeLa cell mRNA, Miaczynska et al. (2004) cloned APPL2. The deduced protein contains 664 amino acids and shares 54% amino acid identity with APPL1 (604299). APPL2 has an N-terminal BAR domain, a central PH domain, and a C-terminal PTB domain. Unlike APPL1, APPL2 has a potential nuclear localization signal.
Miaczynska et al. (2004) identified a pathway directly linking the small GTPase RAB5, a key regulator of endocytosis, to signal transduction and mitogenesis. This pathway operated via APPL1 and APPL2, 2 RAB5 effectors that reside on a subpopulation of endosomes. In response to extracellular stimuli such as EGF (131530) and oxidative stress, APPL1 translocated from the membranes to the nucleus, where it interacted with the nucleosome remodeling and histone deacetylase (NURD) multiprotein complex, a regulator of chromatin structure and gene expression. Both APPL1 and APPL2 were essential for cell proliferation, and their function required RAB5 binding. These findings identified an endosomal compartment bearing RAB5 and APPL proteins as an intermediate in signaling between the plasma membrane and the nucleus.
Bonaglia et al. (2001) stated that the FLJ10659 gene spans 63 kb and contains 21 exons. The ATG start codon is located in exon 1, and the stop codon is located in exon 18.
The APPL2 gene maps to chromosome 12q24.1 (Bonaglia et al., 2001)
Bonaglia et al. (2001) studied a boy with severe expressive language delay consistent with the 22q13.3 deletion syndrome (606232). The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, t(12;22)(q24.1;q13.3). FISH investigation showed that the translocation was reciprocal. Further studies located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and the chromosome 22 breakpoint within exon 21 of the PSAP2 gene (606230). Short homologous sequences were found at the breakpoint on both derivative chromosomes. The authors proposed that disruption of the PSAP2 gene was likely to be responsible for the clinical disorder.
Bonaglia, M. C., Giorda, R., Borgatti, R., Felisari, G., Gagliardi, C., Selicorni, A., Zuffardi, O. Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am. J. Hum. Genet. 69: 261-268, 2001. [PubMed: 11431708] [Full Text: https://doi.org/10.1086/321293]
Miaczynska, M., Christoforidis, S., Giner, A., Shevchenko, A., Uttenweiler-Joseph, S., Habermann, B., Wilm, M., Parton, R. G., Zerial, M. APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 116: 445-456, 2004. [PubMed: 15016378] [Full Text: https://doi.org/10.1016/s0092-8674(04)00117-5]