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Fig. 3 | Cancer Cell International

Fig. 3

From: Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis

Fig. 3

Alterations in dystroglycan-related signal transduction and gene expression in tumor cells. The two subunits of dystroglycan, α-DG and β-DG, are constituent polypeptides of the DGC located at the plasma membrane. In normal cells (A) α-DG glycosylation carried out by DGP-associated proteins is crucial for the anchorage of cells to the ECM, and both integrins and cadherins provide cell-cell adhesion, whereas β-DG contacts the actin cytoskeleton via dystrophin and also acts as a scaffold/multifunctional adaptor in the cytoplasm. Upon cell-ECM interaction and integrin β1 engagement β-DG becomes Tyr-phosphorylated, thereby inhibiting components of the ERK/MAPK and PI3K/AKT pathways through its binding to, and sequestering of, signaling proteins such as Grb2, Src and others. In tumor cells (B) α-DG hypoglycosylation, sometimes found associated with the underexpression of particular DGP-associated proteins or α-DG core protein itself, prevents α-DG binding to laminin with consequent loss of cell attachment to the ECM, whereas E-cadherin downregulation hinders cell-cell adhesion. Also, underexpressed β-DG in tumor cells is unable to prevent activation of ERK/MAPK and PI3K/AKT pathways. Signaling through the ERK/MAPK cascade leads to translocation into the nucleus of MAPKs (such as ERK) and consequent activation of genes promoting cell division and oncogenesis (such as the EGFR, MYC and ZEB1). Also, activation of the PI3K/AKT pathway leads to inhibition of GSK-3β following its phosphorylation by AKT and subsequent activation of Snail, this entering the nucleus and downregulating (through ZEB1) E-cadherin, integrin β1 and LARGE2-encoding genes and promoting adult EMT. In normal cells (A) β-DG also undergoes cleavage by MMPs and phosphorylation by Src, this allowing its dissociation from α-DG and dystrophin and its retrograde targeting to the endoplasmic reticulum and the nucleus, where it localizes both at the nuclear envelope (forming part of a DGC-like complex) and at defined nuclear bodies, where it modulates nuclear structure and activity, including the expression of genes involved in normal cell proliferation. Low levels of β-DG and its abnormal fragmentation in tumor cells (B) prevent its normal modulation of DGP-associated and other genes with a tumor-suppressor role mediated by ETV1 and other transcription factors. However, a subset of other DGP-associated proteins become instead upregulated in tumor cells (B), among which the best known, POMGNT1, inhibits the RPTPβ/ζ phosphatase through its glycosylation carried out by GnT-Vb in the cytoplasm, upregulates MYC and further promotes EMT through the N-glycosylation of N-cadherins. The absence of β-catenin inhibition by GSK-3β and RPTPβ/ζ promotes its tyrosine phosphorylation and migration to the nucleus, where (tyrosine-phosphorylated) β-catenin contributes to upregulate LARGE2 together with Wnt-target, EMT-promoting genes. The loss in tumor cells of cell-ECM and cell-cell adhesion together with EMT occurrence and abnormal function of β-DG in the nucleus, likely resulting in dysregulation of genes involved in normal cell division, favors abnormal cell proliferation, migration and invasiveness, and this paving the way to tumorigenesis. Created with BioRender.com

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