Date Approved


Embargo Period


Document Type


Degree Name

Doctor of Philosophy (Ph.D.), Pharmaceutical Chemistry


Chemistry and Biochemistry


College of Science & Mathematics


Zhihong Wang, Ph.D.

Committee Member 1

Subash Jonnalagadda, Ph.D.

Committee Member 2

Zhiwei Liu, Ph.D.

Committee Member 3

Hao Zhu, Ph.D.

Committee Member 4

Zhijun Li, Ph.D.


BRAF Kinase, MAPK pathway, cell growth and division


Protein kinases–Regulation


Biochemistry, Biophysics, and Structural Biology | Life Sciences


BRAF kinase is a key member of the MAPK pathway, important for cell growth and division. Upstream signals promote BRAF activation by interaction with the membrane bound GTPase, RAS, which leads to relief of autoinhibition and dimerization. The N-terminal regulatory domains of BRAF, including the BRAF specific region (BSR), the RAS binding domain (RBD), and the cysteine rich domain (CRD), govern the conformational state of the cytosolic, autoinhibited monomer and drive the RAS-RAF interaction. Active BRAF phosphorylates and activates its substrate MEK, which in turn phosphorylates and activates ERK. Mutations in RAS and BRAF are the cause of many cancers and RASopathy developmental disorders; however, therapeutic approaches are limited due to challenges in BRAF and RAS inhibition and an incomplete understanding of BRAF and RAS biochemistry. Here, we shed light on the details of BRAF activation and interaction with RAS in three parts: 1) we investigated the roles of the BSR, RBD, and CRD in regulating the RAS-RAF interaction and membrane recruitment; 2) we developed chemical probes to disrupt the RAS-RAF interaction and eliminate MAPK signaling in cancer; and 3) we elucidated the intramolecular interactions involved in RAF autoinhibition. Our findings point to unique contributions of each BRAF N-terminal domain in the regulation of autoinhibition and in determining isoform-specific RAS interactions.

Available for download on Saturday, January 25, 2025