Date

2018

Document Type

Dissertation

Degree

Doctor of Philosophy

Department

Chemistry

First Adviser

Thévenin, Damien

Abstract

Many cell-signaling events are regulated through reversible tyrosine phosphorylation of proteins, which is controlled by the counterbalanced actions of two key enzyme families: Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Interestingly, both families include transmembrane receptor-like enzymes, namely the receptor tyrosine kinases (RTKs) and the receptor-like PTPs (RPTPs). While the regulation and actions of many RTKs are well characterized, the mechanisms controlling the enzymatic activity of RPTPs and how they interact with their substrates remain to be fully explained. Thus, understanding how these receptors function and interact will give fundamental insights into how tyrosine phosphorylation is finely tuned in cells, and how it can be modulated.Homo-dimerization has been shown to regulate the activity of several RPTPs. Even though the transmembrane (TM) and the juxtamembrane (JM) domains have been proposed to be involved in this process, there is no clear structure-based proposal for the role of these regions. Moreover, several RPTPs have been identified as candidate regulators of RTKs. For instance, the phosphorylation of the epidermal growth factor receptor (EGFR) is reduced upon expression of PTPRJ. Particularly, EGFR was shown to physically interact with PTPRJ at the cell surface. However, the contact interface between these receptors is unknown.Here, using a multidisciplinary approach, we show that: (1) PTPRJ homodimerize through specific TM-TM residue interactions, (2) mutations at these TM residues affect PTPRJ activity in cells (e.g., EGFR dephosphorylation), (3) PTPRJ dimerization and activity can be modulated by a TM peptide binder.

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