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Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways.

ABSTRACT: Cripto is a developmental oncoprotein that signals via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Smad2/3 pathways. However, the molecular basis for Cripto coupling to these pathways during embryogenesis and tumorigenesis is not fully understood. In this regard, we recently demonstrated that Cripto forms a cell surface complex with the HSP70 family member glucose-regulated protein-78 (GRP78). Here, we provide novel functional evidence demonstrating that cell surface GRP78 is a necessary mediator of Cripto signaling in human tumor, mammary epithelial and embryonic stem cells. We show that targeted disruption of the cell surface Cripto/GRP78 complex using shRNAs or GRP78 immunoneutralization precludes Cripto activation of MAPK/PI3K pathways and modulation of activin-A, activin-B, Nodal and transforming growth factor-beta1 signaling. We further demonstrate that blockade of Cripto binding to cell surface GRP78 prevents Cripto from increasing cellular proliferation, downregulating E-Cadherin, decreasing cell adhesion and promoting pro-proliferative responses to activin-A and Nodal. Thus, disrupting the Cripto/GRP78 binding interface blocks oncogenic Cripto signaling and may have important therapeutic value in the treatment of cancer.

SUBMITTER: Kelber JA

PROVIDER: S-EPMC2749668 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways.

Kelber J A JA Panopoulos A D AD Shani G G Booker E C EC Belmonte J C JC Vale W W WW Gray P C PC

Oncogene 20090504 24

Cripto is a developmental oncoprotein that signals via mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Smad2/3 pathways. However, the molecular basis for Cripto coupling to these pathways during embryogenesis and tumorigenesis is not fully understood. In this regard, we recently demonstrated that Cripto forms a cell surface complex with the HSP70 family member glucose-regulated protein-78 (GRP78). Here, we provide ...[more]

PMID: 19421146

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Project description: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.

Dataset Information

Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways.

Publications

Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways.

Similar Datasets

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