A new signaling pathway (JAK-Fes-phospholipase D) that is enhanced in highly proliferative breast cancer cells.

Abstract

The products of the oncogene Fes and JAK3 are tyrosine kinases, whose expressions are elevated in tumor growth, angiogenesis, and metastasis. Phosphatidic acid, as synthesized by phospholipase D (PLD), enhances cancer cell survival. We report a new signaling pathway that integrates the two kinases with the lipase. A new JAK3-Fes-PLD2 axis is responsible for the highly proliferative phenotype of MDA-MB-231 breast cancer cells. Conversely, this pathway is maintained at a low rate of expression and activity levels in untransformed cells such as MCF10A. We also deciphered the inter-regulation that exists between the two kinases (JAK3 and the oncogene Fes) and between these two kinases and the lipase (PLD2). Whereas JAK3 and Fes marginally activate PLD2 in non-transformed cells, these kinases greatly enhance (>200%) PLD activity following protein-protein interaction through the SH2 domain and the Tyr-415 residue of PLD2. We also found that phosphatidic acid enhances Fes activity in MDA-MB-231 cells providing a positive activation loop between Fes and PLD2. In summary, the JAK3, Fes and PLD2 interactions in transformed cells maintain PLD2 at an enhanced level that leads to abnormal cell growth. Modulating this new JAK3-Fes-PLD2 pathway could be important to control the highly invasive phenotype of breast cancer cells.

• Authors: Qing Ye, Samuel Kantonen, Karen M Henkels, Julian Gomez-Cambronero
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 14 Pg. 9881-9891 (Apr 05 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23404507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphatidic Acids
• Protein-Tyrosine Kinases
• Janus Kinase 1
• Proto-Oncogene Proteins c-fes
• Phospholipase D

Topics

• Animals
• Breast Neoplasms (metabolism)
• COS Cells
• Cell Line, Tumor
• Cell Proliferation
• Chlorocebus aethiops
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• HL-60 Cells
• Humans
• Janus Kinase 1 (metabolism)
• Neoplasm Invasiveness
• Neoplasms (metabolism)
• Phenotype
• Phosphatidic Acids (chemistry)
• Phospholipase D (chemistry, physiology)
• Plasmids (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins c-fes (metabolism)
• Signal Transduction