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Left-right determination factor A/TGFB4 (Gene LEFTY2)The human LEFTY2 (map locus 1q42.1) gene product, left-right determination factor 2/TGFB4/Lefty2/LeftyA, is a 366 AA long (40.9 kDa) precursor protein that contains a 26 AA signal sequence (1 to 26), a variable propeptide and a 290 AA (long form) left-right determination factor 2 (77 to 366). The propeptide may be processed at two sites leading to long (34 kDa) and short (28 kDa) forms of LEFTYA. The long form results from the action of the proprotein convertases PC5A, Ulloa L, et al. (2001). The 28 kDa form activates the MAPK pathway, Ulloa L, et al. (2001). Proteolytic cleavage of LEFTYA by matrix metalloproteinase MMP2 (gelatinase A) generates peptides that inhibit gelatinolytic and caseinolytic activities of MMPs, Naidu DG, et al. (2008). Processing of the gene product represents a level of control over the Lefty2 activities. Lefty2 has a potential N-glycosylation site at Asn158. Lefty2/TGFB4 is a member of the TGFbeta family of secreted proteins (cytokines) that mediates cell signals via the TGFbeta cell receptors thru Smads 2, 3 and 4. A generalized function of lefty2 is the inhibition of TGFbeta signaling and BMP signaling at the level of the Smad2 and Smad5 respectively, Ulloa L and Tabibzadeh S. (2001). Lefty2 inhibits the phosphorylation of Smad2 following TGFbeta receptor activation; heterodimerization of R-Smad protein Smad4; and nuclear translocation of the Smad complex. It also inhibits BMP-mediated Smad 5 phosphorylation. Lefty2 is expressed in embryonic stem cells (ESC) within the lateral plate mesoderm of gastrulating embryos and in the stoma of the endometrium where it exerts location specific effects. Lefty2 is also found in adenocarcinomas that exhibit mucinous differentiation (colonic, duodenal and ovarian adenocarcinomas) and seminomas and embryonal carcinomas, Tabibzadeh S, et al. (1997). Lefty2 is a key gene expressed in human embryonic stem cells (hESC), Rao RR, et al. (2004) and Fang ZF, et al. (2005), where Nodal, a pluripotency maintenance gene, is also expressed. Nodal inhibits the differentiation of hESC along the neuroectodermal default pathway, Vallier L, et al. (2004); however in the presence of Lefty2, ESC can differentiate into neural precursor cell phenotypes, Smith JR, et al. (2008). Under serum free conditions Dkk1, a Wnt antagonist and Lefty2, a Nodal antagonist, supported the differentiation of mESC cells into Six3+ rostral brain progenitors which subsequently differentiated into Rx+ cells (co-expression Pax6 and Ki67) in the presence of serum and activin, Ikeda H, et al. (2005). Lefty2 was discovered as a factor that is asymmetrically expressed in the left lateral plate mesoderm of gastrulating mouse embryos where it has a role in determination of L-R asymmetry and neurulation. Lefty2 appears just prior to the appearance of lateral asymmetry, Meno C, et al. (1996, 1997). It is identical to Ebaf which was independently identified and localized to chromosome Iq42, Kosaki K, et al. (1999). Lefty2 and pitx2 are expressed in the left heart field, Bisgrove BW, et al. (2000). The regulation of Lefty2 and Nodal are integrated. The left side-specific enhancer (ASE) within the Lefty-2 promoter is sufficient for lefty2 asymmetric expression. The 5.5-kb region of lefty2 corresponds to the inv upstream gene of Lefty2, Saijoh Y, et al. (1999). Nodal up-regulates lefty2 expression. The asymmetric expression of lefty2 is induced by Nodal thru the ASE binding transcription factor FAST2, Saijoh Y, et al. (2000); Yashiro K et al. (2000); Hamada H et al. (2001). Lefty2 and downstream antivin are feedback inhibitors of Nodal signaling, Meno C, et al. (1999). The range of nodal action is normally limited by lefty2, Meno C, et al. (2002). Lefty antagonizes nodal signaling thru competitive binding to the common receptor Act-RIIA or IIB, Sakuma R, et al. (2002). Lefty2/leftyB, also called endometrial bleeding associated factor (Ebaf), was discovered as a factor expressed in human endometrium stroma, Kothapalli R, et al. (1997,) and during late secretory and menstrual phases within endometrial glands, Tabibzadeh S, et al. (1998). The factor was associated with normal menstrual and abnormal endometrial bleeding. Tabibzadeh S, et al. (2000) reported that Ebaf was a secreted product found as 42-, 34-, 28- and 14-kDa proteins in transfected cells, endometrial fluid and serum. Lefty2/Ebaf is involved in the regulation of endometrial differential and embryo implantation. It supports embryo implantation and menstrual tissue shedding (endometrium remodeling) by induction of the expression of matrix metalloproteases (MMP) including proMMP-1,-2, -3, -7, -9 and -14, which break-down extracellular matrix, Tabibzadeh S. (2002), Cornet PB, et al. (2002), and Tang M et al. (2005). Lefty2/Ebaf antagonizes the pro-fibrogenic cytokine, TGF-beta. The expression of Lefty2 is inhibited by progesterone. Endometrial stroma cells differentiate into decidual cells upon progesterone priming, this differentiation involves cAMP and protein kinas A pathways and dramatic elevation of Lefty-2 expression, Brar AK, et al. (2001); Tierney EP, et al. (2003). Decidual differentiation of endometrial stoma is associated with processing of 42 kDa precursor Lefty2 to long form (34 kDa) Lefty2 by the proprotein convertases (PC)5/6A, Tang M et al. (2005). Lefty2 expression is elevated in the oviduct during estrous and early pregnancy, Arganaraz ME, et al. (2007). Sigma offers antibodies and shRNAs useful for the study of LEFTY2 gene products. References: Argañaraz ME, et al. (2007) Rat Lefty2/EBAF gene: isolation and expression analysis in the oviduct during the early pregnancy stage. Genes Genet Syst. 82: 171-175. |
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