Plakophilin3 loss leads to an increase in PRL3 levels promoting K8 dephosphorylation, which is required for transformation and metastasis.
The desmosome anchors keratin filaments in epithelial cells leading to the formation of a tissue wide IF network. Loss of the desmosomal plaque protein plakophilin3 (PKP3) in HCT116 cells, leads to an increase in neoplastic progression and metastasis, which was accompanied by an increase in K8 levels. The increase in levels was due to an increase in the protein levels of the Phosphatase of Regenerating Liver 3 (PRL3), which results in a decrease in phosphorylation on K8. The increase in PRL3 and K8 protein levels could be reversed by introduction of an shRNA resistant PKP3 cDNA. Inhibition of K8 expression in the PKP3 knockdown clone S10, led to a decrease in cell migration and lamellipodia formation. Further, the K8 PKP3 double knockdown clones showed a decrease in colony formation in soft agar and decreased tumorigenesis and metastasis in nude mice. These results suggest that a stabilisation of K8 filaments leading to an increase in migration and transformation may be one mechanism by which PKP3 loss leads to tumor progression and metastasis.
Tata Memorial Centre, Kharghar Node, Navi Mumbai, Maharashtra, India.
Nileema
N
Khapare
Samrat T
ST
Kundu
Lalit
L
Sehgal
Mugdha
M
Sawant
Rashmi
R
Priya
Prajakta
P
Gosavi
Neha
N
Gupta
Hunain
H
Alam
Madhura
M
Karkhanis
Nishigandha
N
Naik
Milind M
MM
Vaidya
Sorab N
SN
Dalal
D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D031541:Fluorescence Resonance Energy Transfer; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053533:Keratin-8 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009369:Neoplasms / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D010766:Phosphorylation; D051191:Plakophilins / Q000172:deficiency* / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017874:Immediate-Early Proteins; C426203:KRT8 protein, human; D053533:Keratin-8; D009841:Oligonucleotides; D051191:Plakophilins; C111534:Ptp4a3 protein, mouse; D017027:Protein Tyrosine Phosphatases