May play a role in early endosome fusion upstream of RAB5, hence regulating receptor trafficking and fluid-phase transport. Enhances cellular sensitivity to TNF-induced apoptosis (PubMed:18288467). (updated: March 4, 2015)
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
No sequence conservation computed yet.
Total structural coverage: 91%
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The reference OMIM entry for this protein is 615208
Pleckstrin homology domain-containing protein, family f, member 2; plekhf2
Endoplasmic reticulum-associated apoptosis-involved protein containing ph and fyve domains; eapf
Ph and fyve domains-containing protein 2; phafin2
Phafin 2
DESCRIPTION
PLEKHF2 has roles in biogenesis of early endosomes (Pedersen et al., 2012) and apoptosis (Li et al., 2008).
CLONING
By database analysis to identify genes similar to phafin-1 (PLEKHF1;
615200), followed by RT-PCR of bone marrow stromal cells, Li et al. (2008) cloned PLEKHF2, which they designated EAPF, or phafin-2. The deduced 249-amino acid protein has a calculated molecular mass of 27.8 kD. It has an N-terminal pleckstrin (PLEK;
173570) homology (PH) domain and a C-terminal FYVE domain and shares 97.6% identity with mouse phafin-2. RT-PCR analysis of 16 human tissues detected abundant expression in placenta, ovary, and small intestine, with weaker expression in heart and pancreas, and no expression in other tissues. Phafin-2 was also expressed in dendritic cells and in most leukemia and solid tumor cell lines examined. Among mouse tissues, highest Phafin2 expression was detected in brain, stomach, and thymus, with weaker expression in spleen, kidney, and skeletal muscle. Fluorescence-tagged mouse or human phafin-2 was expressed in both the cytosol and nucleus of transfected mouse L929 cells.
GENE FUNCTION
Using mouse and human constructs and cell lines, Li et al. (2008) found that TNF-alpha (
191160), lysophosphatidic acid, and phorbol esters induced phafin-2 expression. Overexpression of phafin-2 enhanced cellular sensitivity to TNF-alpha-induced apoptosis, concomitant with partial translocation of phafin-2 to the endoplasmic reticulum (ER). Knockdown of mouse or human phafin-2 protected cells from TNF-alpha-induced apoptosis. Phafin-2 also suppressed the TNF-alpha-induced unfolded protein response in the ER. Mutation analysis revealed that both the PH and FYVE domains of phafin-2 contributed to ER translocation and phafin-2-enhanced apoptosis. Using a lipid-binding assay, Lin et al. (2010) found that PHAFIN2 bound strongly to phosphatidylinositol 3-phosphate, an abundant endosomal lipid. Overexpression of human PHAFIN2 or its isolated FYVE domain caused the formation of enlarged EEA1 (
605070)-positive endosomes in human cell lines. Endosome swelling involved PHAFIN2-mediated activation of the small GTP-binding protein RAB5 (
179512) and, most likely, its downstream regulator PI3 kinase (PI3K; see
601232), as inhibition of RAB5 signaling abolished PHAFIN2-dependent endosome swelling. Overexpression of PHAFIN2 decreased insulin receptor (INSR;
147670) internalization, resulting in increased cell surface INSR density and downstream activation of AP1 (see
165160). Using a library of small interfering RNAs, Pedersen et al. (2012) identified PHAFIN2 among a group of proteins that interfered with EGF (
131530) degradation in HeLa cells. Knockdown of PHAFIN2 inhibited endosome fusion, resulting in reduced size of vesicles that were positive for early endosome markers. Knockdown of PHAFIN2 also delayed, but did not block, fluid-phase transport. Conversely, overexpression of PHAFIN2 resulted in enlarged early endosomes that were positive for internalized EGF and transferrin (TF;
190000). Epitope-tagged PHAFIN2 localized close to the plasma membrane in spots negative for EEA1, suggesting that PHAFIN2 is recruited to early endocytic vesicles prior to EEA1. Pedersen et al. (2012) concluded that PHAFIN2 has a role in fusion of early endosomes.
MAPPING
Hartz (2013) mapped the PLEKHF2 gene to chromosome 8q22.1 based on an alignment of the PLEKHF2 sequence (GenBank GENBANK AK
023249) with the genom ...
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Subscribe to this protein entry history
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 615208 was added.