The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

From Springer Nature via Jisc Publications RouterHistory: received 2020-04-21, rev-recd 2021-03-23, accepted 2021-04-14, registration 2021-04-15, pub-electronic 2021-05-12, online 2021-05-12, pub-print 2021-06-10Publication status: PublishedFunder: Worldwide Cancer Research; doi: https://doi.org/10.13039/100011713; Grant(s): 15-1283Funder: RCUK | MRC | Medical Research Foundation; doi: https://doi.org/10.13039/501100009187; Grant(s): MC_PC_18056Abstract: There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior

ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy.

Resistance to Imatinib Mesylate (IM) is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described. In the present report we aim to study the role of several MAPK in IM resistance not associate to BCR/ABL mutations. Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM (K562, Lama 84) as well as primary material from resistant and responder patient without BCR/ABL mutations. Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype. However, Erk2, but not Erk1, is critical for the acquired resistance to IM. In fact, Bcr/Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein. Finally, we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM. In summary our data support the use of therapeutic approaches based on Erk2 inhibition, which could be added to the therapeutic armamentarium to fight CML, especially when IM resistance develops secondary to Erk2 activation

The Extracellular Linker of pro-Neuregulin-α2c Is Required for Efficient Sorting and Juxtacrine Function

The neuregulins (NRGs) play important roles in animal physiology, and their disregulation has been linked to diseases such as cancer or schizophrenia. The NRGs may be produced as transmembrane proteins (proNRGs), even though they lack an N-terminal signal sequence. This raises the question of how NRGs are sorted to the plasma membrane. It is also unclear whether in their transmembrane state, the NRGs are biologically active. During studies aimed at solving these questions, we found that deletion of the extracellular juxtamembrane region termed the linker, decreased cell surface exposure of the mutant proNRG(ΔLinker), and caused its entrapment at the cis-Golgi. We also found that cell surface–exposed transmembrane NRG forms retain biological activity. Thus, a mutant whose cleavage is impaired but is correctly sorted to the plasma membrane activated ErbB receptors in trans and also stimulated proliferation. Because the linker is implicated in surface sorting and the regulation of the cleavage of transmembrane NRGs, our data indicate that this region exerts multiple important roles in the physiology of NRGs

Astrocytes express Mxi2, a splice isoform of p38MAPK

Mitogen-activated protein kinases (MAPKs) are a superfamily of cytoplasmic serine/threonine kinases that transduce many types of extracellular stimuli into cellular responses. p38MAPK is a member of this family with its active form in a diphosphorylated state (p38MAPKdiP). Two strong anti-p38MAPKdiP immunoreactive bands (apparent molecular weight 38 and 34 kDa) were detected by Western blotting in cultured astrocytes. Using a specific antibody and employing immunoprecipitation procedures and SELDI-TOF analysis, the 34 kDa band was found to correspond to Mxi2, a splice variant of p38MAPK; cultured astrocytes therefore express Mxi2. Separate protein extractions of different subcellular fractions, and fluorescent immunovisualisation employing confocal microscopy, showed Mxi2 to have a non-nuclear, cytosolic distribution in the studied cells. ERK1/2, protein whose intracellular distribution is influenced by Mxi2, showed the same cytoplasmic pattern than Mxi2