Mutant p53 interactome identifies nardilysin as a p53R273H-specific binding partner that promotes invasion.
The invasiveness of tumour cells depends on changes in cell shape, polarity and migration. Mutant p53 induces enhanced tumour metastasis in mice, and human cells overexpressing p53R273H have aberrant polarity and increased invasiveness, demonstrating the 'gain of function' of mutant p53 in carcinogenesis. We hypothesize that p53R273H interacts with mutant p53-specific binding partners that control polarity, migration or invasion. Here we analyze the p53R273H interactome using stable isotope labelling by amino acids in cell culture and quantitative mass spectrometry, and identify at least 15 new potential mutant p53-specific binding partners. The interaction of p53R273H with one of them--nardilysin (NRD1)--promotes an invasive response to heparin binding-epidermal growth factor-like growth factor that is p53R273H-dependant but does not require Rab coupling protein or p63. Advanced proteomics has thus allowed the detection of a new mechanism of p53-driven invasion.
Quantitative Proteomics Group, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
Cynthia R
CR
Coffill
Patricia A J
PA
Muller
Hue Kian
HK
Oh
Suat Peng
SP
Neo
Kelly A
KA
Hogue
Chit Fang
CF
Cheok
Karen H
KH
Vousden
David P
DP
Lane
Walter P
WP
Blackstock
Jayantha
J
Gunaratne
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D004815:Epidermal Growth Factor / Q000378:metabolism; D006639:Histidine; D013058:Mass Spectrometry / Q000379:methods; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D040901:Proteomics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D006639:Histidine; D004815:Epidermal Growth Factor; D008666:Metalloendopeptidases; C570669:NRDC protein, human; C087976:nardilysin