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Structural and mechanistic studies of the RAS/RAF MAPkinase pathway

Award Number: R01CA315392
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Structural and mechanistic studies of the RAS/RAF MAPkinase pathway - Project Summary We are studying the structure and regulation of the RAS/RAF/MEK/ERK (RAS/MAP kinase) pathway to obtain an atomic resolution understanding of how these proteins recognize and interact with one another and how these interactions are controlled by phosphorylation events. In addition, we seek to understand the complicated pharmacology of drugs that target this pathway with a long-term goal of informing development of more effective and better tolerated therapeutics. Somatic mutations in KRAS, BRAF and other components of this pathway are common drivers of diverse cancers. In addition, germline mutations in pathway components cause a spectrum of related developmental syndromes collectively termed RASopathies. Despite decades of study, critical structural and mechanistic questions remain unanswered, limiting therapeutic development. Our laboratory previously determined the first structures of intact BRAF complexes in autoinhibited and active states, revealing mechanisms of 14-3-3-mediated regulation and dimerization. Here we propose to achieve an atomic-resolution understanding of additional key regulatory mechanisms in this pathway through three interconnected aims. Aim 1 will elucidate how RAFs are activated through heterodimerization with each other and with the pseudokinases KSR1/2. Building on our emerging BRAF/CRAF heterodimer structure, we will investigate how heterodimer asymmetry affects drug sensitivity and paradoxical activation by RAF inhibitors. We will biochemically reconstitute and structurally characterize BRAF/KSR complexes to define the role of these poorly understood pseudokinases in RAF activation. Aim 2 will reveal the structural basis for RAF regulation by two poorly understood phosphorylation events, tyrosine phosphorylation of the N-terminal acidic motifs in ARAF and CRAF that promotes their activation, and ERK-mediated phosphorylation that provides feedback inhibition. Using structural biology combined with quantitative mass spectrometry, we will measure stimulus-induced phosphorylation changes in these and other sites across pathway components, and elucidate the effects of these events on the structure and activity of RAF complexes. Aim 3 will reveal how MEK accomplishes dual-specificity phosphorylation of its sole substrate ERK on both threonine and tyrosine. Despite MEK's central role in this pathway, no structures exist for active, phosphorylated MEK. Using AI-enabled protein design and cryo-EM, we will determine structures of active MEK and MEK/ERK complexes to understand this unique stereochemical feat. Successful execution of these aims will bring structural clarity to key events in the MAPK pathway from initiation of RAF signaling to ERK activation and subsequent feedback inhibition of RAF. In addition, they will inform development of next-generation therapeutics that avoid liabilities of current drugs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $657,443 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	8/27/2026	NEW	$657,443
														Subtotal = $657,443

Grand Total All Awards = $657,443

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Structural and mechanistic studies of the RAS/RAF MAPkinase pathway

Award Number: R01CA315392

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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