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1. Introduction
Celiac disease (CD) is a chronic and immune-mediated enteropathy that is induced by dietary protein gluten (from wheat, barley and rye) in genetically predisposed individuals [1]. It is a small-intestine disorder, affecting approximately 1% of the European population with some regional variations [2] and causing malnutrition and severe complications. Celiac patients have a greater burden of disease than the general population, and a long-term gluten-free diet (GFD) is the only therapy for this disease [1,3]. HLA-DQ2 and HLA-DQ8 molecules are responsible for only approximately 40% of genetic predisposing factors in the pathogenesis of CD [4], which is necessary but not sufficient to cause disease [5,6]. Thus, many more risk loci outside the HLA region should be identified as disease markers.
In recent years, genome-wide association studies (GWAS) have expanded our understanding of genetic makeup and revealed several possible inherited risk factors in celiac disorders [7,8,9,10]. Many of the non-HLA loci overlap with Crohn’s disease, type 1 diabetes, rheumatoid arthritis and juvenile idiopathic arthritis [11,12,13,14,15], such as lipoma preferred partner (LPP) and T-cell activation Rho GTPase activating protein (TAGAP). Alterations of the actin cytoskeleton and cell shape can be observed in the CD patients’ intestinal mucosa [16,17], while the cell shape is maintained through the actin cytoskeleton and focal adhesion [18]. LPP is localized with paxillin in focal adhesions, and the number of paxillin focal adhesions with LPP is increased in CD fibroblasts. A constitutive alteration in cell shape and adhesion involving LPP occurs in CD fibroblasts, suggesting a correlation between LPP and CD pathogenesis [19]. In addition, LPP is considered a substrate of the protein-tyrosine-phosphatase 1B (PTP1B) [20]. Of note, loss of PTP1B can attenuate the activation of extracellular signal regulated kinase (ERK) [21], which is activated in the CD patients’ mucosa on a GFD or a gluten-containing diet (GCD). Only when ERK is phosphorylated can it transduce to the nuclei, and it has been found that more nuclei of the enterocytes from CD patients were positive for ERK compared with controls. Inhibition of ERK phosphorylation normalizes crypt enterocyte proliferation of CD atrophic mucosa [22]. When PTP1B is sufficient or excessive, there may be more ERK activity in the celiac enterocytes, resulting in the progression of CD.
TAGAP is involved in the Rho...