A new regulatory mechanism for Raf kinase activation, retinoic acid-bound Crabp1

Sung Wook Park, Jennifer Nhieu, Shawna D. Persaud, Michelle C. Miller, Youlin Xia, Yi Wei Lin, Yu Lung Lin, Hiroyuki Kagechika, Kevin H. Mayo, Li Na Wei

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


The rapidly accelerated fibrosarcoma (Raf) kinase is canonically activated by growth factors that regulate multiple cellular processes. In this kinase cascade Raf activation ultimately results in extracellular regulated kinase 1/2 (Erk1/2) activation, which requires Ras binding to the Ras binding domain (RBD) of Raf. We recently reported that all-trans retinoic acid (atRA) rapidly (within minutes) activates Erk1/2 to modulate cell cycle progression in stem cells, which is mediated by cellular retinoic acid binding protein 1 (Crabp1). But how atRA-bound Crabp1 regulated Erk1/2 activity remained unclear. We now report Raf kinase as the direct target of atRA-Crabp1. Molecularly, Crabp1 acts as a novel atRA-inducible scaffold protein for Raf/Mek/Erk in cells without growth factor stimulation. However, Crabp1 can also compete with Ras for direct interaction with the RBD of Raf, thereby negatively modulating growth factor-stimulated Raf activation, which can be enhanced by atRA binding to Crabp1. NMR heteronuclear single quantum coherence (HSQC) analyses reveal the 6-strand β-sheet face of Crabp1 as its Raf-interaction surface. We identify a new atRA-mimicking and Crabp1-selective compound, C3, that can also elicit such an activity. This study uncovers a new signal crosstalk between endocrine (atRA-Crabp1) and growth factor (Ras-Raf) pathways, providing evidence for atRA-Crabp1 as a novel modulator of cell growth. The study also suggests a new therapeutic strategy by employing Crabp1-selective compounds to dampen growth factor stimulation while circumventing RAR-mediated retinoid toxicity.

Original languageEnglish (US)
Article number10929
JournalScientific reports
Issue number1
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
This work was supported by DK54733, DK60521, Dean’s Commitment, and the Distinguished McKnight Professorship of University of Minnesota to LNW. Data were collected at the Minnesota NMR Center, University of Minnesota. Funding for NMR instrumentation was provided by the Office of the Vice President for Research, the Medical School, the College of Biological Science, NIH, NSF, and the Minnesota Medical Foundation.

Publisher Copyright:
© 2019, The Author(s).


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