Cripto‑1 overexpression in U87 glioblastoma cells activates MAPK, focal adhesion and ErbB pathways

Alowaidi,Faisal; Hashimi,Saeed  M.; Alqurashi,Naif; Wood,Stephen  A.; Wei,Ming  Q.

doi:10.3892/ol.2019.10626

Cripto‑1 overexpression in U87 glioblastoma cells activates MAPK, focal adhesion and ErbB pathways

Authors:
- Faisal Alowaidi
- Saeed M. Hashimi
- Naif Alqurashi
- Stephen A. Wood
- Ming Q. Wei
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Affiliations: Department of Pathology and Laboratory Medicine, College of Medicine and University Hospital, King Saud University, Riyadh 11461, Saudi Arabia, Department of Basic Science, Biology Unit, Deanship of Preparatory Year and Supporting Studies, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia, Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia, Division of Molecular and Gene Therapies, School of Medical Science, Griffith University, Gold Coast, Queensland 4222, Australia
Published online on: July 16, 2019 https://doi.org/10.3892/ol.2019.10626
Pages: 3399-3406

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Abstract

Discovering the underlying signalling pathways that control cancer cells is crucial for understanding their biology and to develop therapeutic regimens. Thus, the aim of the present study was to determine the effect of Cripto‑1 on pathways controlling glioblastoma (GBM) cell function. To this end, changes in protein phosphorylation in cells overexpressing Cripto‑1 were analysed using the Kyoto Encyclopedia of Genes and Genomes pathway analysis tool, as well as the Uniprot resource to identify the functions of Cripto‑1‑dependent phosphorylated proteins. This revealed that proteins affected by Cripto‑1 overexpression are involved in multiple signalling pathways. The mitogen‑activated protein kinase (MAPK), focal adhesion (FA) and ErbB pathways were found to be enriched by Cripto‑1 overexpression with 35, 27 and 24% of pathway proteins phosphorylated, respectively. These pathways control important cellular processes in cancer cells that correlate with the observed functional changes described in earlier studies. More specifically, Cripto‑1 may regulate MAPK cellular proliferation and survival pathways by activating epithelial growth factor receptor (EGFR; Ser1070) or fibroblast GFR1 (Tyr654). Its effect on cellular proliferation and survival could be mediated through Src (Tyr418), FA kinase (FAK; Tyr396), p130CAS (Tyr410), c‑Jun (Ser63), Paxillin (PXN; Tyr118) and BCL2 (Thr69) of the FA pathway. Cripto‑1 may also control cellular motility and invasion by activating Src (Tyr418), FAK (Tyr396) and PXN (Tyr118) of the FA pathway. However, Cripto‑1 regulation of cellular invasion and migration might be not limited to the FA pathway, it may also control these cellular mechanisms through signalling via EGFR (Ser1070)/Her2 (Tyr877) to mediate the Src (Tyr418) and FAK (Tyr396) cascade activation of the ErbB signalling pathway. Angiogenesis could be mediated by Cripto‑1 by activating c‑Jun (Ser63) through EGFR (Ser1070)/Her2 (Tyr877) of the ErbB pathway. To conclude, the present study has augmented and enriched our current knowledge on the crucial roles that Cripto‑1 may play in controlling different cellular mechanisms in GBM cells.

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