Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common β-subunit

Perugini, Michelle; Brown, Anna L.; Salerno, Diana; Booker, Grant W.; Stojkoski, Cvetan; Hercus, Timothy R.; Lopez, Angel F.; Hibbs, Margaret L.; Gonda, Thomas J.; D’Andrea, Richard J.

doi:10.1182/blood-2009-08-235846

Cited by 60 publications

(43 citation statements)

References 40 publications

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“…3A, left). In particular, Lyn, the predominant Src kinase expressed in myeloid cells (27) shown previously to mediate GMPbc receptor activation and subsequent signaling (22), bound Cbl preferentially in the presence of GM-CSF (Fig. 3A, right).…”

Section: Resultsmentioning

confidence: 99%

“…21), JMML cells do not display hypersensitivity to IL-3 or IL-5. Notably, Src binds to the ligand-specifying GMRa chain, which upon ligand binding associates with GMRbc to initiate GMRbc activation via JAK2 and Src (22,31). However, it is unclear whether IL-3R or IL-5R directly interacts Src or Cbl and whether the interplay observed between Cbl and Src on GMR is recapitulated on IL-3/5R.…”

Section: Discussionmentioning

confidence: 99%

“…Upon binding of GM-CSF to GMRa, a higher-order signaling complex is formed that promotes the activation of nonreceptor tyrosine kinases JAK2 and Src family kinases c-Src and Lyn, which subsequently phosphorylate GMRbc (22). Activated GMR serves as a docking site for adaptors and signaling molecules resulting in activation of downstream signaling, including the ERK pathway (23).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of SRC Corrects GM-CSF Hypersensitivity That Underlies Juvenile Myelomonocytic Leukemia

et al. 2013

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm in children characterized by the overproduction of monocytic cells that infiltrate the spleen, lung, and liver. JMML remains a disease for which few curative therapies are available other than myeloablative hematopoietic stem cell transplant (HSCT); however, relapse remains a major cause of treatment failure and the long-term morbidities of HSCT for survivors are substantial. A hallmark feature of JMML is acquired hypersensitivity by clonal myeloid progenitor cells to granulocyte macrophage-colony stimulating factor (GM-CSF) via a largely unknown mechanism. Here, we identify c-Cbl (henceforth referred to as Cbl) as a GM-CSF receptor (GMR) adaptor protein that targets Src for ubiquitin-mediated destruction upon GM-CSF stimulation and show that a loss of negative regulation of Src is pivotal in the hyperactivation of GMR signaling in Cbl-mutated JMML cells. Notably, dasatinib, an U.S. Food and Drug Administration-approved multikinase inhibitor that also targets Src family, dramatically attenuated the spontaneous and GM-CSF-induced hypersensitive growth phenotype of mononuclear cells from peripheral blood and bone marrow collected from JMML patients harboring Cbl or other known JMML-associated mutations. These findings reveal Src kinase as a critical oncogenic driver underlying JMML. Cancer Res; 73(8); 2540-50. Ó2013 AACR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Inhibition of SRC Corrects GM-CSF Hypersensitivity That Underlies Juvenile Myelomonocytic Leukemia

et al. 2013

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“…A point mutation in the SH3 domain of SLAP diminished the interaction with GM-CSFRa, suggesting that is a likely mode of interaction. A recent study by Perugini et al (36) showed that the SH3 domain of Src and Lyn bind to GM-CSFRa. Given that the SH3 domain of SLAP is most similar to the SH3 domain of the Src family kinases, SLAP might also compete with Src and/or Lyn for binding at this site within GM-CSFRa.…”

Section: Discussionmentioning

confidence: 99%

The Src-Like Adaptor Protein Regulates GM-CSFR Signaling and Monocytic Dendritic Cell Maturation

Liontos

Dissanayake

Ohashi

et al. 2011

The Journal of Immunology

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GM-CSF is an important cytokine involved in myeloid differentiation and inflammatory processes. Signaling through the GM-CSFR also plays a critical role in the generation of monocyte-derived dendritic cells (DC). In this article, we report that the Src-like adaptor protein (SLAP) functions as a negative regulator of the GM-CSFR. In bone marrow-derived DC (BM-DC) lacking SLAP and the closely related SLAP2, downregulation of GM-CSFRβ is impaired, leading to enhanced phosphorylation of Jak2 and prolonged activation of Akt and Erk1/2 in response to GM-CSF stimulation. Compared with wild-type bone marrow, SLAP/SLAP2−/− bone marrow gave rise to similar numbers of CD11c+ and CD11b+ DC, but SLAP/SLAP2−/− BM-DC failed to acquire high levels of MHC class II, CD80, and CD86, indicating an impairment in maturation. Furthermore, MHC class II expression in SLAP/SLAP2−/− BM-DC was rescued by decreasing GM-CSF concentration, suggesting that enhanced GM-CSF signaling mediates the block in maturation. In addition, SLAP/SLAP2−/− BM-DC produced less IL-12 and TNF-α in response to LPS compared with controls and failed to stimulate T cells in an MLR. Ag-specific T cell activation assays showed that SLAP/SLAP2−/− BM-DC were less robust at inducing IFN-γ secretion by DO11.10 T cells. These results indicated that SLAP-mediated GM-CSFR regulation is important for the generation of functionally mature monocytic DC.

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“…10 On ligand binding, the GM-CSF receptor (GMR) activates nonreceptor tyrosine kinases Janus kinase 2 (JAK2) and Src family kinases Src and Lyn, which subsequently phosphorylate the b-subunit of GMR. 11 Activated GMR serves as a docking site for adaptors and signaling molecules such as SHP-2, which results in activation of downstream Ras signaling pathways. Ras proteins function as molecular switches by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate-bound conformations.…”

Section: Defining the Molecular Genetics Of Jmml: Insights From The Bmentioning

confidence: 99%

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

Chang

Dvorak

Loh

2014

Blood

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Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukemia, a similar disease in adults. Although the current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transplant, relapse is the most frequent cause of treatment failure. Tremendous progress has been made in defining the genomic landscape of JMML. Insights from cancer predisposition syndromes have led to the discovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signaling pathway. This has improved our ability to accurately diagnose patients, develop molecular markers to measure disease burden, and choose therapeutic agents to test in clinical trials. This review emphasizes recent advances in the field, including mapping of the genomic and epigenome landscape, insights from new and existing disease models, targeted therapeutics, and future directions.

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Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common β-subunit

Cited by 60 publications

References 40 publications

Inhibition of SRC Corrects GM-CSF Hypersensitivity That Underlies Juvenile Myelomonocytic Leukemia

Inhibition of SRC Corrects GM-CSF Hypersensitivity That Underlies Juvenile Myelomonocytic Leukemia

The Src-Like Adaptor Protein Regulates GM-CSFR Signaling and Monocytic Dendritic Cell Maturation

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

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