The LAR protein tyrosine phosphatase enables PDGF β-receptor activation and signal transduction

Zheng, Wei (2013). The LAR protein tyrosine phosphatase enables PDGF β-receptor activation and signal transduction. University of Birmingham. Ph.D.

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Many cellular activities including cell survival, proliferation, migration and differentiation are controlled by growth factors and their corresponding tyrosine kinases receptor (RTKs). Growth factor receptor activation is strictly regulated by protein tyrosine phosphatases (PTPs). Here I investigated whether the receptor protein tyrosine phosphatase (RPTP) LAR, which is known to modify the activity of several RTKs, also regulates platelet derived growth factor (PDGF) receptor activity and signalling. Mouse embryonic fibroblasts (MEFs) expressing mutant LAR lacking its phosphatase domains (LARΔP) showed reduced phosphorylation of PDGFβ receptor (PDGFβR) compared with wild type (WT) cells. This was rescued by re-expression of WT LAR. The decreased phosphorylation of the PDGFβR was independent of ligand concentration and occurred on all tyrosine residues, suggesting that LAR is required for full PDGFβR kinase activation. The decreased kinase activity reduced the amplitude or duration of the different signalling pathways activated downstream of the PDGFβR, and resulted in reduced proliferation in response to PDGF-BB. These findings demonstrate, for the first time, that LAR activity is required for PDGF-induced fibroblast proliferation. The inhibition of PDGFβR kinase activity in LARΔP cells was exerted via increased basal activity of the tyrosine kinase c-Abl and its substrate protein kinase Cδ (PKCδ). Ligand-induced PDGFβR dimerization is defective in LARΔP cells, possibly due to the observed increase in the Nherf2 protein associating with the PDGFβR. In summary, I have identified LAR as a new regulator of PDGFβR activity, and propose a novel mechanism where PDGF-induced activation of c-Abl serves as a negative feedback loop to terminate the PDGFβR kinase activity. This may occur via PKCδ activation promoting the association of Nherf2 with PDGFβR, thereby reducing ligand-induced receptor dimerization and kinase activation. In this model, LAR promotes PDGFβR activity by inactivating c-Abl.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Life & Environmental Sciences
School or Department: School of Biosciences
Funders: None/not applicable
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history > QH301 Biology


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