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PMID:16732323

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Citation

Pasder, O, Shpungin, S, Salem, Y, Makovsky, A, Vilchick, S, Michaeli, S, Malovani, H and Nir, U (2006) Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells. Oncogene 25:4194-206

Abstract

Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclin-dependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1alpha was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1alpha and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.

Links

PubMed Online version:10.1038/sj.onc.1209695

Keywords

Breast Neoplasms/drug therapy; Breast Neoplasms/enzymology; Breast Neoplasms/pathology; Cell Line, Tumor; Down-Regulation/physiology; Enzyme Activation/physiology; Female; G0 Phase/physiology; G1 Phase/physiology; Humans; Male; Phosphoprotein Phosphatases/metabolism; Prostatic Neoplasms/drug therapy; Prostatic Neoplasms/enzymology; Prostatic Neoplasms/pathology; Protein Phosphatase 1; Protein-Tyrosine Kinases/antagonists & inhibitors; Protein-Tyrosine Kinases/physiology; RNA, Small Interfering/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PP1A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P70451

F

Seeded From UniProt

complete

MOUSE:FER

involved_in

GO:0001932: regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FER

enables

GO:0008157: protein phosphatase 1 binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P62136

F

Seeded From UniProt

complete


See also

References

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