Research Papers:
Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation
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Abstract
Malalage N. Peiris1, April N. Meyer1, Dalida Warda1, Alexandre Rosa Campos2 and Daniel J. Donoghue1,3
1 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92037, USA
2 Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
3 UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA
Correspondence to:
Daniel J. Donoghue, | email: | [email protected] |
Keywords: oncogenic fusion protein; chromosomal translocation; protein interactome; phosphoproteome; stem cell leukemia/lymphoma
Received: March 06, 2022 Accepted: April 19, 2022 Published: May 11, 2022
ABSTRACT
Translocation of Fibroblast Growth Factor Receptors (FGFRs) often leads to aberrant cell proliferation and cancer. The BCR-FGFR1 fusion protein, created by chromosomal translocation t(8;22)(p11;q11), contains Breakpoint Cluster Region (BCR) joined to Fibroblast Growth Factor Receptor 1 (FGFR1). BCR-FGFR1 represents a significant driver of 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma, which progresses to acute myeloid leukemia or T-cell lymphoblastic leukemia/lymphoma. Mutations were introduced at Y177F, the binding site for adapter protein Grb2 within BCR; and at Y766F, the binding site for the membrane associated enzyme PLCγ1 within FGFR1. We examined anchorage-independent cell growth, overall cell proliferation using hematopoietic cells, and activation of downstream signaling pathways. BCR-FGFR1-induced changes in protein phosphorylation, binding partners, and signaling pathways were dissected using quantitative proteomics to interrogate the protein interactome, the phosphoproteome, and the interactome of BCR-FGFR1. The effects on BCR-FGFR1-stimulated cell proliferation were examined using the PLCγ1 inhibitor U73122, and the irreversible FGFR inhibitor futibatinib (TAS-120), both of which demonstrated efficacy. An absolute requirement is demonstrated for the dual binding partners Grb2 and PLCγ1 in BCR-FGFR1-driven cell proliferation, and new proteins such as ECSIT, USP15, GPR89, GAB1, and PTPN11 are identified as key effectors for hematopoietic transformation by BCR-FGFR1.
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