ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration

Abstract

ER O-glycosylation can be induced through relocalisation GalNAc-Transferases from the Golgi. This process markedly stimulates cell migration and is constitutively activated in more than 60% of breast carcinomas. How this activation is achieved remains unclear. Here, we screened 948 signalling genes using RNAi and imaging. We identified 12 negative regulators of O-glycosylation that all control GalNAc-T sub-cellular localisation. ERK8, an atypical MAPK with high basal kinase activity, is a strong hit and is partially localised at the Golgi. Its inhibition induces the relocation of GalNAc-Ts, but not of KDEL receptors, revealing the existence of two separate COPI-dependent pathways. ERK8 down-regulation, in turn, activates cell motility. In human breast and lung carcinomas, ERK8 expression is reduced while ER O-glycosylation initiation is hyperactivated. In sum, ERK8 appears as a constitutive brake on GalNAc-T relocalisation, and the loss of its expression could drive cancer aggressivity through increased cell motility.DOI: http://dx.doi.org/10.7554/eLife.01828.001

PCNA-interacting peptides reduce Akt phosphorylation and TLR-mediated cytokine secretion suggesting a role of PCNA in cellular signaling

“…A potential role for cytosolic PCNA in cellular signaling. Schematic overview of known connections between the pattern recognition receptors TLRs, PKR and RIG-1 (illustrated in dark blue) and the PI3K/Akt, MAPK and NFκB signaling pathways [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]32,[37][38][39][40][41]57,58,68,69,71,78,79]. Proteins containing the APIM-sequence associated with these pathways are illustrated in pink [11].…”

“…three direct members of the PI3K/Akt pathway (p110-α, p110-γ, and PI3K-C2β), proteins regulating PTEN (MAST3 and PLK3), and proteins of the mitogen-activated protein kinase (MAPK) pathways (ERK8, MK2, MK5, MST4, SOS1, NF1, and TAO1 and 2) [13][14][15][16][17][18][19][20] (see pink proteins in Fig. 1).…”

MAPK15 is an attractive therapeutic target for gastric cancer

“…Low to moderate expression levels of MAPK15 are detected in normal tissues, such as breast, lung, liver, stomach, colon, and kidney [12,13] . In addition, Chia et al reported that MAPK15 downregulation in breast and lung carcinomas can drive the cancers aggressively by activating cell motility [14] . In contrast, MAPK15 is highly expressed in anaplastic thyroid carcinoma cell lines (ARO, Cal62, and Kat4) and a colon cancer cell line (HCT15) but is expressed at a very low level in the JB6 Cl41 normal mouse epidermal cell line [15,16] .…”

“…Extensive arrays of specific ERK1/2, JNK, and p38 inhibitors have been evaluated in preclinical and clinical trials, but the value of a MAPK15 inhibitor to treat cancer has not been tested. Some studies have used Ro-318220 to inhibit MAPK15 kinase activity but this molecule is a typical selective protein kinase C inhibitor [14,24,33] . A three-dimensional analysis of the MAPK15 domain revealed a high percentage of scaffolds to develop specific kinase inhibitors [34] .…”

“…Currently, 14 MAPKs have been characterized in mammalian cells. The conventional MAPKs are comprised of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun amino (N)-terminal kinases 1/2/3 (JNK1/2/3), p38 isofomrs (a, β, γ, and δ)], and ERK5.…”