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MEMBRANE-ASSOCIATED RING-CH FINGER PROTEIN 2; MARCHF2

MEMBRANE-ASSOCIATED RING-CH FINGER PROTEIN 2; MARCHF2

Alternative titles; symbolsMARCH II; MARCH2HGNC Approved Gene Symbol: MARCHF2Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:8,413,304-8,439,0...

Alternative titles; symbols

  • MARCH II; MARCH2

HGNC Approved Gene Symbol: MARCHF2

Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:8,413,304-8,439,016 (from NCBI)

▼ Description
MARCH2 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases (EC 6.3.2.19). MARCH enzymes add ubiquitin (see 191339) to target lysines in substrate proteins, thereby signaling their vesicular transport between membrane compartments. MARCH2 reduces surface accumulation of several glycoproteins and appears to regulate early endosome-to-trans-Golgi network (TGN) trafficking (Bartee et al., 2004; Nakamura et al., 2005).

▼ Cloning and Expression
Poxviruses and gamma-2 herpesviruses express ubiquitin ligases called K3 proteins that inhibit the surface expression of glycoproteins, including major histocompatibility complex class I molecules (see 142800). By searching a database for sequences similar to the functional domains of viral K3 proteins, Bartee et al. (2004) identified 9 human MARCH proteins, including MARCH2. The deduced MARCH2 protein contains a short N terminus, followed by a RING-CH domain and 2 transmembrane domains. MARCH2 shares about 60% identity with MARCH3 (613333) in the RING-CH and transmembrane domains. Real-time PCR analysis showed that MARCH2 was expressed at variable levels in all tissues examined, with highest expression in heart. Immunofluorescence analysis revealed colocalization of epitope-tagged MARCH2 with an endoplasmic reticulum marker and with a lysosome marker.

Using RT-PCR, De Gassart et al. (2008) detected MARCH2 expression in immature and mature human dendritic cells and in HeLa and human B-cell lines, but not in monocytes.

Nakamura et al. (2005) cloned rat March2. Northern blot analysis of rat tissues revealed ubiquitous March2 expression. Cell fractionation experiments showed that March2 associated with endosomes and with plasma membrane vesicles.

▼ Gene Function
Bartee et al. (2004) showed that the isolated RING-CH domain of MARCH2 functioned as an E3 ubiquitin ligase in a reaction containing ubiquitin, ATP, an E1 ubiquitin-activating enzyme (see UBE1; 314370), and the E2 ubiquitin-conjugating enzyme UBCH2 (UBE2H; 601082), UBCH3 (CDC34; 116948), or UBCH5A (UBE2D1; 602961). Following transfection into HeLa cells, MARCH2 downregulated the surface expression of cotransfected B7.2 (CD86; 601020) and endogenous TFR (TFRC; 190010).

Using immunoprecipitation analysis of a rat liver membrane fraction, Nakamura et al. (2005) showed that rat March2 interacted directly with syntaxin-6 (STX6; 603944). Overexpression of March2 in COS-7 cells resulted in redistribution of syntaxin-6 and some syntaxin 6-interacting SNARE proteins (e.g., VAMP3; 603657) into March2-positive vesicles. Retrograde transport of Tgn38 (TGOLN2; 603062) and epitope-tagged furin (FUR; 136950) to the TGN was perturbed. March2 overexpression in HeLa cells reduced cell surface expression of TFR and transferrin (TF; 190000) uptake and interfered with delivery of internalized transferrin to perinuclear recycling endosomes. March2 overexpression had no effect on EGF (131530)-stimulated EGFR (131550) degradation via lysosomes. In a number of cell lines, including HeLa cells, March2 overexpression caused cell rounding and detachment from the culture dish. Depletion of endogenous MARCH2 in HeLa cells by small interfering RNA perturbed the TGN localization of transfected rat Tgn38 and endogenous syntaxin-6 and TGN46, the human homolog of rat Tgn38. Mutation of a C-terminal class I PDZ-binding motif altered the subcellular localization of March2, with some March2 accumulation within the endoplasmic reticulum. Nakamura et al. (2005) concluded that MARCH2 is likely a regulator of early endosome-to-TGN vesicle trafficking.

▼ Mapping
Hartz (2010) mapped the MARCH2 gene to chromosome 19p13.2 based on an alignment of the MARCH2 sequence (GenBank AF151074) with the genomic sequence (GRCh37).

Tags: 19p13.2