Tumour cells have increased abundance of growth-promoting receptors at the cell surface which can contribute to oncogenesis and/or resistance to targeted therapy. We have shown that the tyrosine phosphatase PTPN14 (also called Pez), which is mutated in various cancers, suppresses metastasis of breast cancer xenografts by reducing intracellular protein trafficking to the plasma membrane (Belle et al, 2015). We have now found that PTPN14, its substrate pY-PKCd and the tyrosine kinaseĀ Fer that phosphorylates PKCd (to counteract PTPN14) are central regulators of receptor tyrosine kinase trafficking. Our data show that the Fer-PKCd-PTPN14 axis controls the balance between RTK degradation and recycling by regulating Rab5-Rab7 switching during early to late endosome maturation. Data will be presented on the mechanism through which this axis controls endosome maturation. Importantly, we find that in a subset of triple negative breast cancer cell lines and a cohort of triple negative breast cancer patients, pY-PKCd levels are elevated and this corresponds to the increased presence of a stabilised hybrid Rab5-Rab7 endosomal compartment indicative of stalled endosomal maturation, and increased activation of multiple RTKs. Our new data reveal that the Fer-PKCd-TPTPN14 axis is dysregulated in a cohort of TNBC and is driving cancer progression through dysregulated RTK trafficking - this suggests that targeting the PTPN14-PKCd-TK axis may lead to novel therapeutics for this cohort of TNBC patients. Targeting this axis may also overcome compensatory signalling by other RTKs in patients that are resistant to anti-EGFR therapy. We will also present data on a new PTPN14 knock-out mouse, which has elevated pY-PKCd levels and hyperplasia in multiple organs and the role of endosomal trafficking in the resultant phenotype.
Ref: Belle L et al (2015) Sci Signaling 33:ra18