Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Pasder, Orel; Shpungin, Sally; Salem, Yaniv; Makovsky, A; Vilchick, S; Michaeli, Shulamit; Malovani, Hana; Nir, Uri

doi:10.1038/sj.onc.1209695

Cited by 42 publications

(46 citation statements)

References 57 publications

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“…Interestingly, Nir and colleagues have reported a role for FER in the proliferation of breast carcinoma and prostate cell lines. 29 In our study, we found that some AML cell lines and fresh AML blasts have activated FES and/or FER. Therefore, the activation status and the requirement for FES kinases should be investigated downstream of other oncogenic tyrosine kinases.…”

Section: Activation Of Fes Kinases In Aml E Voisset Et Almentioning

confidence: 70%

FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.

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Section: Activation Of Fes Kinases In Aml E Voisset Et Almentioning

confidence: 70%

FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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“…The kinase was detected in all human malignant cell lines analyzed (20,21), and its levels in malignant prostate tumors are significantly higher than those detected in benign growths (22). Furthermore, downregulation of Fer impairs the proliferation of prostate, breast, and colon carcinoma cells (23), induces death in colon carcinoma and non-small cell lung cancer (NSCLC) cells (24,25), abolishes the ability of prostate carcinoma PC3 and V-Sis-transformed cells to form colonies in soft agar (22), and prevents the metastatic spread of breast and lung adenocarcinoma tumors (26,27). At the clinical level, high Fer expression levels have been linked to poor prognosis of hepatocellular carcinoma (HCC; ref.…”

Section: Introductionmentioning

confidence: 96%

Oncogenic Properties of a Spermatogenic Meiotic Variant of Fer Kinase Expressed in Somatic Cells

et al. 2014

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The kinase Fer and its spermatogenic meiotic variant, FerT, are coexpressed in normal testes and cancerous tumors, but whether they exert related roles in spermatogenic or malignant cells has not been known. Here, we show that Fer and FerT reside in the mitochondria of spermatogenic cells and are harnessed to the reprogrammed mitochondria of colon carcinoma cells. Both kinases bound complex I of the mitochondrial electron transport chain (ETC) in spermatogenic and in colon carcinoma cells, and silencing of either Fer or FerT was sufficient to impair the activity of this complex. Directed mitochondrial accumulation of FerT in nonmalignant NIH3T3 cells increased their ETC complex I activity, ATP production, and survival, contingent upon stress conditions caused by nutrient and oxygen deprivation. Strikingly, directed mitochondrial accumulation of FerT endowed nonmalignant cells with tumor-forming ability. Thus, recruitment of a meiotic mitochondrial component to cancer cell mitochondria highlights a pivotal role for reprogrammed mitochondria in tumorigenesis. Cancer Res; 74(22);

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“…In addition, the stable downregulation of Fer using antisense cDNA impairs PC-3 cell growth and colony formation in vitro (11). RNA interference against Fer similarly inhibits cell proliferation, causing a G 0 -G 1 cell cycle arrest via the retinoblastoma protein, cyclindependent kinases (CDK4 and CDK2), and phosphatase PP1a (15).…”

Section: Introductionmentioning

confidence: 99%

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Zoubeidi

Rocha²,

Zouanat³

et al. 2009

Molecular Cancer Research

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Androgen withdrawal is the most effective form of systemic therapy for men with advanced prostate cancer. Unfortunately, androgen-independent progression is inevitable, and the development of hormone-refractory disease and death occurs within 2 to 3 years in most men. The understanding of molecular mechanisms promoting the growth of androgenindependent prostate cancer cells is essential for the rational design of agents to treat advanced disease. We previously reported that Fer tyrosine kinase level correlates with the development of prostate cancer and aggressiveness of prostate cancer cell lines. Moreover, knocking down Fer expression interferes with prostate cancer cell growth in vitro. However, the mechanism by which Fer mediates prostate cancer progression remains elusive. We present here that Fer and phospho-Y705 signal transducer and activator of transcription 3 (STAT3) are barely detectable in human benign prostate tissues but constitutively expressed in the cytoplasm and nucleus of the same subsets of tumor cells in human prostate cancer. The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6). Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution. The modulation of Fer expression/activation resulted in inhibitory or stimulatory effects on STAT3 phosphorylation, nuclear translocation, and transcriptional activation. These effects translated in IL-6 -mediated PC-3 cell growth. Taken together, these results support an important function of Fer in prostate

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Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Cited by 42 publications

References 57 publications

FES kinases are required for oncogenic FLT3 signaling

FES kinases are required for oncogenic FLT3 signaling

Oncogenic Properties of a Spermatogenic Meiotic Variant of Fer Kinase Expressed in Somatic Cells

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

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