Regulation of Epidermal Growth Factor Receptor Mediated Cell
Signaling by Protein Tyrosine Phosphatases
Matthew J. Lazzara
Assistant Professor, Department of Chemical and Biomolecular Engineering
University of Pennsylvania
The epidermal growth factor receptor (EGFR) initiates cell signaling pathways associated with
proliferation, migration, and differentiation and is frequently over-expressed or mutated in
cancer. EGFR-mediated signaling is promoted by ligand binding to the receptor extracellular
domain, receptor dimerization, and auto-phosphorylation of receptor cytoplasmic tyrosines.
These tyrosines serve as docking sites for signaling pathway adaptors which are regulated by
phosphorylation as well. While the processes leading to EGFR and adaptor phosphorylation
have been studied extensively, the critically important process of dephosphorylation by
phosphatases is much less well understood. Indeed, virtually nothing is known about the rates at
which proteins are dephosphorylated at different cellular locations by specific phosphatases.
This talk will highlight two examples of our work on developing quantitative understanding of
the regulation of EGFR-mediated cell signaling by protein tyrosine phosphatases.
The first example will address the fundamental question of the kinetics with which EGFR is
dephosphorylated at different locations within the cell. In the classical understanding of this
process, receptor dephosphorylation occurs only in the cell interior after ligand-mediated
receptor endocytosis. Recent work from our lab calls this view into question. By constructing a
novel mechanistic model of EGFR phosphorylation dynamics and regressing it against
experimental measurements of receptor phosphorylation response to EGFR ligands, phosphatase
inhibitors, and EGFR kinase inhibitors, we have determined that the rate of receptor
dephosphorylation at the plasma membrane may be at least as high as that in the cell interior and
that receptor dephosphorylation occurs on a timescale which is small compared to receptor
endocytosis. These findings have important implications for the regulation of receptor-level
phenomena including kinase inhibition and receptor trafficking, as will be discussed.
The second example will focus on the role of the cytosolic protein tyrosine phosphatase SHP2 in
EGFR-mediated signaling. Downstream of EGFR, SHP2 augments the activity of the MAP
kinase pathway, which regulates cell cycle progression and cell survival. Our lab recently
demonstrated that EGFR-activating mutations which arise in certain cancers perturb the
functional role of SHP2 in ways that impact cancer cell response to EGFR-targeted therapeutics.
This perturbation involves the sequestration of biochemically active SHP2 with constitutively
active EGFR mutants, which display impairment in ligand-mediated endocytosis. This
sequestration phenomenon occurs in both lung and brain cancer cells with structurally distinct
EGFR mutations.
The results of our work point to new opportunities and challenges for understanding and
regulating EGFR-mediated signaling in clinically important ways by developing quantitative
understanding of the role of phosphatases. The methods and insights developed as part of our
work on EGFR will be useful as we expand our efforts to signaling processes mediated by other
receptors.