Zaritza Petrova (Yale University, USA)

Program

"Understanding how kinase domain interactions contribute to dimerization and activation of receptor tyrosine kinases"

The Epidermal Growth Factor Receptor (EGFR) is a receptor tyrosine kinase (RTK) that mediates signals for cell proliferation, differentiation, migration, and survival.
While its activation mechanism has served as a paradigm for RTK activation, EGFR has unique features that make it susceptible to oncogenic mutations, leading to dysregulated activity and cancer, particularly NSCLC. My research focuses on the role of asymmetric kinase dimerization in EGFR activation. Using biochemical and biophysical technique - including SAXS, HDX-MS, AUC, and steady-state enzyme kinetics - I measure the homo-dimerization affinity of the EGFR kinase domains. I show that while kinase dimerization is weak and transient, it significantly enhances kinase activity. Dimerized EGFR, previously considered a slow kinase, exhibits activity comparable to other tyrosine kinases, whereas both wildtype and mutationally activated monomers are far less active. Consequently, mutations that enhance dimerization can produce a much stronger signaling effect than those acting on monomeric kinases. To further investigate this mechanism, I study a disulfide-linked synthetic dimer and an oncogenic kinase domain duplication (KDD) in which two kinase domains are connected by a disordered linker. Using SAXS and Cryo-EM, I demonstrate that KDD’s high oncogenic activity depends on transient, not constitutive, asymmetric kinase dimer formation. These findings highlight the importance of kinase dimerization dynamics in understanding RTK signaling and suggest that this knowledge can also inform EGFR-targeted therapies.

About the speaker:

Zaritza Petrova completed her graduate studies in Mark Lemmon’s laboratory in the Department of Pharmacology at Yale University, where she investigated the mechanism of EGFR activation. She earned her B.A. in Biology from Dartmouth College, where she developed an interest in human physiology and was a member of the cross-country team. Between Dartmouth and Yale, she worked as a research technician at the University of Pittsburgh in Graham Hatfull’s laboratory, using bacteriophages to study the genetics of Mycobacterium tuberculosis. Broadly, Zaritza Petrova is interested in the structural and dynamic aspects of receptor activation mechanisms and how the evolution of different signaling cascades leads to distinct cellular outcomes.