Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar; Mali, Raghuveer Singh; Martin, Holly; Kobayashi, Michihiro; Vemula, Sasidhar; Canela, Victor Hugo; Waskow, Emily R.; Visconte, Valeria; Tiu, Ramon V.; Smith, Catherine C.; Shah, Neil P.; Bunting, Kevin D.; Boswell, H. Scott; Liu, Yan; Chan, Rebecca J.; Kapur, Reuben

doi:10.1016/j.celrep.2014.10.039

Cited by 53 publications

(70 citation statements)

References 48 publications

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“…However, a role for active STAT5 in metastasis of other cancers has been established, and active STAT5a promotes prostate cancer invasion and migration40. Whilst CaMKII does not phosphorylate STAT5a at the site examined in this study, a FAK-mediated pathway can control STAT5 activation in leukaemia cells41. Furthermore, FAK42 and Akt43 are essential for inducing EMT in hepatocytes and cancer cells, respectively.…”

Section: Discussionmentioning

confidence: 68%

Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells

Chi

Evans

Gilchrist

et al. 2016

Sci Rep

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Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a multi-functional kinase that controls a range of cellular functions, including proliferation, differentiation and apoptosis. The biological properties of CaMKII are regulated by multi-site phosphorylation. However, the role that CaMKII phosphorylation plays in cancer cell metastasis has not been examined. We demonstrate herein that CaMKII expression and phosphorylation at T286 is increased in breast cancer when compared to normal breast tissue, and that increased CAMK2 mRNA is associated with poor breast cancer patient prognosis (worse overall and distant metastasis free survival). Additionally, we show that overexpression of WT, T286D and T286V forms of CaMKII in MDA-MB-231 and MCF-7 breast cancer cells increases invasion, migration and anchorage independent growth, and that overexpression of the T286D phosphomimic leads to a further increase in the invasive, migratory and anchorage independent growth capacity of these cells. Pharmacological inhibition of CaMKII decreases MDA-MB-231 migration and invasion. Furthermore, we demonstrate that overexpression of T286D, but not WT or T286V-CaMKII, leads to phosphorylation of FAK, STAT5a, and Akt. These results demonstrate a novel function for phosphorylation of CaMKII at T286 in the control of breast cancer metastasis, offering a promising target for the development of therapeutics to prevent breast cancer metastasis.

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Section: Discussionmentioning

confidence: 68%

Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells

Chi

Evans

Gilchrist

et al. 2016

Sci Rep

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“…FLT3-ITD leads to constitutive activation of JAK/STAT signaling, driving growth and transformation of hematopoietic cells. [35][36][37] In keeping with this, our transcriptome analysis revealed that genes involved in JAK/STAT signaling (Stat5a, Cish, Socs2) were differentially expressed in Figure 8B). We confirmed by RNA-seq that this was due to activation of a JAK/STAT program in Npm1 cA/1 ;Nras G12D/1 AML cells (supplemental Figure 9).…”

Section: Hoxa Gene Expression Is Unaltered In Npm1-mutant Early Multimentioning

confidence: 75%

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

Dovey

Cooper

Mupo

et al. 2017

Blood

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Key Points• Npm1c and Nras-G12D comutation in mice leads to AML with a longer latency and a more mature phenotype than the Npm1c/Flt3-ITD combination.• Mutant Flt3 or Nras allele amplification is the dominant mode of progression in both Npm1c/Flt3-ITD and Npm1c/ Nras-G12D murine AML.NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. . During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1 cA/1 ;Nras G12D/1 mice showed acquisition of other human AML mutations, including IDH1 R132Q. We also find, using primary Cas9-expressing AMLs, that Hoxa genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with NPM1c/FLT3-ITD vs NPM1/NRAS-G12D-mutant AML and functionally confirm the role of HOXA genes in

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“…28 Interestingly, 3 of the 4 AML cell lines and several patient samples we tested in this study do not contain either FLT3-ITD or KITD816V mutations yet were still sensitive to PAK1 inhibition. Furthermore, the AML patient samples we studied included FAB subtypes M4 and M5, which more frequently have elevated PAK1 expression from our assessments of a large cohort of AML patients (GSE14468; supplemental Figure 7A-B).…”

Section: Discussionmentioning

confidence: 99%

PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

Pandolfi

Stanley

et al. 2015

Blood

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Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis

Cited by 53 publications

References 48 publications

Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells

Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

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