Roscovitine enhances All-trans retinoic acid (ATRA)-induced leukemia cell differentiation: Novel effects on signaling molecules for a putative Cdk2 inhibitor

Rashid, Asif; Duan, Xin; Gao, Feng; Yang, Moon-Sik; Yen, Andrew

doi:10.1016/j.cellsig.2020.109555

Cited by 9 publications

(13 citation statements)

References 67 publications

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“…The amount of Numb and Lyn that were complexed together increased with RA-treatment for wt parental cells, but not for Fgr KO cells. It is known that RA causes the tyr 416 phosphorylation of Lyn, which is a telltale of kinase activation [ 45 ]. Fgr binding to Numb is thus associated with phosphorylation of Lyn, where Slp-76 and Lyn are the closest associates of Fgr in the signalsome force node representation of known co-IP partnerings.…”

Section: Resultsmentioning

confidence: 99%

“…Numb binds Vav, which is known to co-immunoprecipitated with the putative Raf, Lyn, Fgr, Slp-76, Cbl “Spine” molecules [ 45 ]. Cells were grown in parallel untreated and RA-treated (10 -6 M) cultures.…”

Section: Resultsmentioning

confidence: 99%

“…It focuses in particular on a novel paradigm whereby a novel MAPK pathway related signaling machine enables the RA signaling targeting transcriptional activation that is seminal to inducing leukemic cell differentiation. We have previously reported on the components of this novel signaling machine [ 38 , 39 , 45 ]. The challenges to this novel paradigm were how such a complex machine formed and what triggers its activation.…”

Section: Discussionmentioning

confidence: 99%

“…A modest SiRNA down regulation of Lyn was found to modestly inhibit RA-induced differentiation [ 38 ]. However, paradoxically, an essentially total knockdown resulted in enhanced differentiation [ 45 ]. But this loss of Lyn was associated with enhancing RA-induced Fgr expression, suggesting a possible compensatory functional redundancy between these two SFKs.…”

Section: Discussionmentioning

confidence: 99%

“…A similar MAPK dependence occurs for 1,25-dihydroxy vitamin D3-induced monocytic differentiation, indicating that the effect is not lineage specific, but fundamental to differentiation along either possible lineage that the cell is capable of [ 37 ]. The signal originates with a putative signalsome that embodies a number of MAPK pathway-related signaling molecules as well as some others ( Scheme 1 ) [ 38 – 45 ]. The Raf/Mek/Erk axis is imbedded in the signalsome and becomes activated.…”

Section: Introductionmentioning

confidence: 99%

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Role for Fgr and Numb in retinoic acid-induced differentiation and G0 arrest of non-APL AML cells

Kazim

Yen

2021

Oncotarget

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Retinoic acid (RA) is a fundamental regulator of cell cycle and cell differentiation. Using a leukemic patient-derived in vitro model of a non-APL AML, we previously found that RA evokes activation of a macromolecular signaling complex, a signalosome, built of numerous MAPK-pathway-related signaling molecules; and this signaling enabled Retinoic-Acid-Response-Elements (RAREs) to regulate gene expression that results in cell differentiation/cell cycle arrest. Toward mechanistic insight into the nature of this novel signaling, we now find that the NUMB cell fate determinant protein is an apparent scaffold for the signalosome. Numb exists in the cell bound to an ensemble of signalosome molecules, including Raf, Lyn, Slp-76, and Vav. Addition of RA induces the expression of Fgr. Fgr binds NUMB, which is associated with (p-tyr) phosphorylation of NUMB and enhanced NUMB-binding and (p-tyr)phosphorylation of select signalosome components, thereby betraying signalosome activation. Signalosome activation is associated with cell differentiation along the myeloid lineage and G1/0 cell cycle arrest. If RA-induced Fgr expression is ablated by a CRISPR-KO; then the RA-induced (p-tyr) phosphorylation of NUMB and enhanced NUMB-binding and (p-tyr)phosphorylation of select signalosome components are lost. The cells now fail to undergo RA-induced differentiation or G1/0 arrest. In sum we find that NUMB acts as a scaffold for a signaling machine that functions to propel RA-induced differentiation and G1/0 arrest, and that Fgr binding to NUMB turns the function on. The Numb fate determinant protein thus appears to regulate the retinoic acid embryonic morphogen using the Fgr Src-Family-Kinase. These mechanistic insights suggest therapeutic targets for a hitherto incurable AML.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%