GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:18206965

From GONUTS
Jump to: navigation, search
Citation

Lim, ST, Chen, XL, Lim, Y, Hanson, DA, Vo, TT, Howerton, K, Larocque, N, Fisher, SJ, Schlaepfer, DD and Ilic, D (2008) Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol. Cell 29:9-22

Abstract

FAK is known as an integrin- and growth factor-associated tyrosine kinase promoting cell motility. Here we show that, during mouse development, FAK inactivation results in p53- and p21-dependent mesodermal cell growth arrest. Reconstitution of primary FAK-/-p21-/- fibroblasts revealed that FAK, in a kinase-independent manner, facilitates p53 turnover via enhanced Mdm2-dependent p53 ubiquitination. p53 inactivation by FAK required FAK FERM F1 lobe binding to p53, FERM F2 lobe-mediated nuclear localization, and FERM F3 lobe for connections to Mdm2 and proteasomal degradation. Staurosporine or loss of cell adhesion enhanced FERM-dependent FAK nuclear accumulation. In primary human cells, FAK knockdown raised p53-p21 levels and slowed cell proliferation but did not cause apoptosis. Notably, FAK knockdown plus cisplatin triggered p53-dependent cell apoptosis, which was rescued by either full-length FAK or FAK FERM re-expression. These studies define a scaffolding role for nuclear FAK in facilitating cell survival through enhanced p53 degradation under conditions of cellular stress.

Links

PubMed PMC2234035 Online version:10.1016/j.molcel.2007.11.031

Keywords

Amino Acid Sequence; Animals; Apoptosis/drug effects; Cell Division/physiology; Cell Nucleus/metabolism; Cell Survival/physiology; Cisplatin/pharmacology; Cyclin-Dependent Kinase Inhibitor p21/deficiency; Cyclin-Dependent Kinase Inhibitor p21/genetics; Cyclin-Dependent Kinase Inhibitor p21/physiology; Embryonic Development/genetics; Embryonic Development/physiology; Fibroblasts/cytology; Fibroblasts/drug effects; Fibroblasts/metabolism; Focal Adhesion Kinase 1/chemistry; Focal Adhesion Kinase 1/deficiency; Focal Adhesion Kinase 1/genetics; Focal Adhesion Kinase 1/physiology; Mesoderm/pathology; Mice; Mice, Knockout; Molecular Sequence Data; Proteasome Endopeptidase Complex/metabolism; Protein Structure, Tertiary; Sequence Alignment; Sequence Homology, Amino Acid; Staurosporine/pharmacology; Tumor Suppressor Protein p53/metabolism; Ubiquitin/metabolism; Ubiquitination

Significance

Annotations

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

MOUSE:FAK1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FAK1

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FAK1

involved_in

GO:2000060: positive regulation of ubiquitin-dependent protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FAK1

involved_in

GO:0042127: regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.