Signalling from receptor tyrosine kinases can be regulated by exercising a balance in receptor recycling and degradation after internalisation of activated cell surface receptors. Recycling of receptors back to the cell surface can facilitate continued signal transduction, while the degradation of receptors attenuates signalling.
We have identified a novel signalling axis involving the tyrosine kinase Fer and tyrosine phosphatase PTPN14 (also known as Pez), which regulate the trafficking of multiple RTKs through phosphorylation/dephosphorylation of the serine/threonine kinase PKCd on Y374. We find that elevated levels of pY374-PKCd correlates with (1) increased detection of a Rab5-Rab7 double positive endosomal compartment, (2) enhanced recycling and reduced degradation of internalised RTKs, and (3) increased anchorage independent growth of breast cancer cells in vitro. In a cohort of triple negative breast cancer patients, we found that approximately a third displayed both elevated pY374-PKCd and Rab5-Rab7 double positive endosomes, suggesting that these patients may have dysregulated RTK trafficking.
We have evidence to suggest that PKCd phosphorylated on Y374 has a distinct set of substrates that exert its effects on RTK trafficking, and current studies aim to identify pY374-PKCd specific substrates using differential phosphoproteomics. Identification of novel pY374-PKCd substrates will add to our understanding of how the balance between receptor recycling and degradation is regulated, and may provide novel therapeutic targets for patients with dysregulated RTK trafficking, who we suggest may be refractory to current single-agent therapies targeting a specific receptor.