Proliferation and Survival Signaling from Both Jak2-V617F and Lyn Involving GSK3 and mTOR/p70S6K/4EBP1 in PVTL-1 Cell Line Newly Established from Acute Myeloid Leukemia Transformed from Polycythemia Vera

Nagao, Takaaki; Kurosu, Tetsuya; Umezawa, Yōji; Nogami, Ayako; Oshikawa, Gaku; Tohda, Shuji; Yamamoto, Masahide; Miura, Osamu

doi:10.1371/journal.pone.0084746

Cited by 24 publications

(36 citation statements)

References 34 publications

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“…As it is known that in B cells, the Tyr273 residue within ITIM of FcgRIIb2 is phosphorylated by LYN to inhibit cell proliferation (24), we started to analyze the kinase activity of LYN in neuronal cells after exposure to oAb . LYN activity is often determined by the level of the autophosphorylation at the Tyr397 residue (25). Treatment of both primary mouse cortical neurons and SH-SY5Y human neuroblastoma cells with oAb 1-42 greatly enhanced the autophosphorylation of LYN at Tyr397 (Fig.…”

Section: Lyn Kinase Is Activated In Neuronal Cells By Oab Treatment Amentioning

confidence: 99%

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Gwon

Kim

et al. 2018

FASEB j.

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SRC‐family kinases (SFKs) have been implicated in Alzheimer's disease (AD), but their mode of action was scarcely understood. Here, we show that LYN plays an essential role in amyloid β (Aβ)‐triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to Aβ 1–42 (Aβ1–42). Knockdown of LYN expression inhibited Aβ1–42‐induced neuronal cell death. Of note, LYN interacted with FcγRIIb2 upon exposure to Aβ1–42 and phosphorylated FcγRIIb2 at Tyr273 within immunoreceptor tyrosine‐based inhibitory motif in neuronal cells. With the use of the structure‐based drug design, we isolated KICG2576, an ATP‐competitive inhibitor of LYN. Determination of cocrystal structure illustrated that KICG2576 bound to the cleft in the LYN kinase domain and inhibited LYN with a half‐maximal inhibitory concentration value of 0.15 µM. KICG2576 inhibited Aβ‐ or FcγRIIb2‐induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to Aβ, KICG2576 blocked the phosphorylation of FcγRIIb2 and translocation of phosphatidylinositol 3,4,5‐trisphosphate 5‐phosphatase 2, a binding protein to the phosphorylated FcγRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of Aβ1–42‐FcγRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated Aβ‐induced memory impairment. These results suggest that LYN plays a crucial role in Aβ1–42‐mediated neurotoxicity and tau pathology, providing a therapeutic potential of LYN in AD.—Gwon, Y., Kim, S.‐H., Kim, H. T., Kam, T.‐I., Park, J., Lim, B., Cha, H., Chang, H.‐J., Hong, Y. R., Jung, Y.‐K. Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN. FASEB J. 33, 4300–4313 (2019). http://www.fasebj.org

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Section: Lyn Kinase Is Activated In Neuronal Cells By Oab Treatment Amentioning

confidence: 99%

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Gwon

Kim

et al. 2018

FASEB j.

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“…Targeting mTOR has also demonstrated positive anti-MPN effects as a single agent and in combination with JAK2 inhibition. 45,[65][66][67][68][69] The potency of the combination of INCB053914 and ruxolitinib was also manifested in in vivo MPN models driven by aberrant JAK2 signaling. The combination of INCB053914 and ruxolitinib antagonized the growth of SET2 cell xenograft tumors at doses of each drug that had little to no effect as monotherapies ( Figure 6A).…”

Section: Incb053914 and Ruxolitinib Suppress Jak2 V617f -Driven Tumormentioning

confidence: 99%

The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN

et al. 2019

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“…A persistently active mutant of STAT5 (STAT5a s711F ) associates with Gab2 in myeloid leukemias and promotes growth in vitro via the activation of AKT activation ( 66 ). Nagao T et al found that apoptosis may be suppressed in PVTL-1 cells, an AML cell line, through inactivation of GSK3 by Lyn, and of JAK2-V617F and is also suppressed by the activation of STAT5 by JAK2-V617F ( 67 ). Tyrosine-phosphorylated-STAT5 can be tracked using flow cytometry or immunostaining and is a biomarker associated with poor prognosis in patients with juvenile myelomonocytic leukemia (JMML) ( 66 ) and AML ( 68 ).…”

Section: Gab2 In Cancermentioning

confidence: 99%

Structure and function of Gab2 and its role in cancer (Review)

Ding

Feng

et al. 2015

Molecular Medicine Reports

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The docking proteins of the Grb-associated binder (Gab) family transduce cellular signals between receptors and intracellular downstream effectors, and provide a platform for protein-protein interactions. Gab2, a key member of the Gab family of proteins, is involved in the amplification and integration of signal transduction, evoked by a variety of extracellular stimuli, including growth factors, cytokines and antigen receptors. Gab2 protein lacks intrinsic catalytic activity; however, when phosphorylated by protein-tyrosine kinases (PTKs), Gab2 recruits several Src homology-2 (SH2) domain-containing proteins, including the SH2-containing protein tyrosine phosphatase 2 (SHP2), the p85 subunit of phosphoinositide-3 kinase (PI3K), phospholipase C-γ (PLCγ)1, Crk, and GC-GAP. Through these interactions, the Gab2 protein triggers various downstream signal effectors, including SHP2/rat sarcoma viral oncogene/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and PI3K/AKT, involved in cell growth, differentiation, migration and apoptosis. It has been previously reported that aberrant Gab2 and/or Gab2 signaling is closely associated with human tumorigenesis, particularly in breast cancer, leukemia and melanoma. The present review aimed to focus on the structure and effector function of Gab2, its role in cancer and its potential for use as an effective therapeutic target.

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Proliferation and Survival Signaling from Both Jak2-V617F and Lyn Involving GSK3 and mTOR/p70S6K/4EBP1 in PVTL-1 Cell Line Newly Established from Acute Myeloid Leukemia Transformed from Polycythemia Vera

Cited by 24 publications

References 34 publications

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN

Structure and function of Gab2 and its role in cancer (Review)

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