Fer governs mTORC1 regulating pathways and sustains viability of pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a high percentage of morbidity. The deciphering and identification of novel targets and tools for intervening with its adverse progression are therefore of immense importance. To address this goal we adopted a specific inhibitor of the intracellular tyrosine kinase Fer, whose expression level is upregulated in PDAC tumors, and is associated with poor prognosis of patients.

The Fer tyrosine kinase protects sperm from spontaneous acrosome reaction.

The physiological acrosome reaction occurs after mammalian spermatozoa undergo a process called capacitation in the female reproductive tract. Only acrosome reacted spermatozoon can penetrate the egg zona-pellucida and fertilize the egg. Sperm also contain several mechanisms that protect it from undergoing spontaneous acrosome reaction (sAR), a process that can occur in sperm before reaching proximity to the egg and that abrogates fertilization.

Loss of Fer Jeopardizes Metabolic Plasticity and Mitochondrial Homeostasis in Lung and Breast Carcinoma Cells.

Metabolic plasticity is a hallmark of the ability of metastatic cancer cells to survive under stressful conditions. The intracellular Fer kinase is a selective constituent of the reprogramed mitochondria and metabolic system of cancer cells. In the current work, we deciphered the modulatory roles of Fer in the reprogrammed metabolic systems of metastatic, lung (H358), non-small cell lung cancer (NSCLC), and breast (MDA-MB-231), triple-negative breast cancer (TNBC), carcinoma cells.

TMF1 is upregulated by insulin and is required for a sustained glucose homeostasis.

Insulin-regulated glucose homeostasis is a critical and intricate physiological process, of which not all regulatory components have been deciphered. One of the key players in modulating glucose uptake by cells is the glucose transporter-GLUT4. In this study, we aimed to explore the regulatory role of the trans-Golgi-associated protein-TATA Element Modulatory Factor (TMF1) in the GLUT4 mediated, insulin-directed glucose uptake.

Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells.

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT.

A novel Fer/FerT targeting compound selectively evokes metabolic stress and necrotic death in malignant cells.

Disruption of the reprogrammed energy management system of malignant cells is a prioritized goal of targeted cancer therapy. Two regulators of this system are the Fer kinase, and its cancer cell specific variant, FerT, both residing in subcellular compartments including the mitochondrial electron transport chain. Here, we show that a newly developed inhibitor of Fer and FerT, E260, selectively evokes metabolic stress in cancer cells by imposing mitochondrial dysfunction and deformation, and onset of energy-consuming autophagy which decreases the cellular ATP level.

TMF/ARA160 Governs the Dynamic Spatial Orientation of the Golgi Apparatus during Sperm Development.

TMF/ARA160 is known to be a TATA element Modulatory Factor (TMF). It was initially identified as a DNA-binding factor and a coactivator of the Androgen receptor. It was also characterized as a Golgi-associated protein, which is essential for acrosome formation during functional sperm development.

Oncogenic properties of a spermatogenic meiotic variant of fer kinase expressed in somatic cells.

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.

Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF-/- mice.

Tata Element Modulatory Factor (TMF/ARA160) is a multifunctional Golgi-associated protein, which accumulates in colonic enterocytes and goblet cells. Mice lacking TMF/ARA160 (TMF(-/-)) produce thick and uniform colonic mucus that resists adherent bacterial colonization and diminishes susceptibility of these mice to induced acute colitis, through a mechanism that is not fully understood. Here, we show that mucus secretion by goblet cells is altered in the colon of TMF(-/-) mice, resulting in the formation of a highly oligomerized colonic gel-forming mucin, MUC2.

Testosterone deficiency accompanied by testicular and epididymal abnormalities in TMF(-/-) mice.

TMF/ARA160 is a Golgi-associated protein, which is essential for spermiogenesis. In this study, we show that lack of TMF/ARA160 leads to defects in both the testis and the epididymis. In the testis, spermatid retention and extensive proliferation of Leydig cells were observed.

Loss of TMF/ARA160 protein renders colonic mucus refractory to bacterial colonization and diminishes intestinal susceptibility to acute colitis.

TMF/ARA160 is a Golgi-associated protein with several cellular functions, among them direction of the NF-κB subunit, p65 RelA, to ubiquitination and proteasomal degradation in stressed cells. We sought to investigate the role of TMF/ARA160 under imposed stress conditions in vivo. TMF(-/-) and wild-type (WT) mice were treated with the ulcerative agent dextran sulfate sodium (DSS), and the severity of the inflicted acute colitis was determined.

Down-regulation of Fer induces ROS levels accompanied by ATM and p53 activation in colon carcinoma cells.

Fer is an intracellular tyrosine kinase which resides in both the cytoplasm and nucleus of mammalian cells. This kinase was also found in all malignant cell-lines analyzed and was shown to support cell-cycle progression in cancer cells. Herein we show that knock-down of Fer, both, impairs cell-cycle progression and imposes programmed cell death in colon carcinoma (CC) cells.

Intronic promoter drives the BORIS-regulated expression of FerT in colon carcinoma cells.

Fer is an intracellular tyrosine kinase that accumulates in most mammalian tissues. A truncated variant of Fer, FerT, is uniquely detected in spermatogenic cells and is absent from normal somatic tissues. Here, we show that in addition to Fer, FerT also accumulates in CC cells and in metastases derived from colorectal tumors, but not in normal human cells.

TMF/ARA160: A key regulator of sperm development.

TMF/ARA160 is a Golgi-associated protein to which several cellular activities have been attributed. These include, trafficking of Golgi-derived vesicles and E3 ubiquitin ligase activity. Here we show that TMF/ARA160 is required for the onset of key processes which underlie the development of mature sperm in mammals.

TMF/ARA160 downregulates proangiogenic genes and attenuates the progression of PC3 xenografts.

TMF/ARA160 is a Golgi-associated protein whose level is downregulated in solid tumors. TMF changes its subcellular localization on exposure of cells to stress cues, thereby, directing proteins, such as the key transcription factor, Stat3, to proteasomal degradation. Here, we show that enforced ectopic expression of HA-TMF in PC3 prostate carcinoma cells, which do not express Stat3, significantly attenuated the development and growth of xenograft tumors elicited by these cells in athymic mice.

Hsp90 and a tyrosine embedded in the Hsp90 recognition loop are required for the Fer tyrosine kinase activity.

Hsp90 is a key regulator of tyrosine kinases activity and is therefore considered as a promising target for intervention with deregulated signaling pathways in malignant cells. Here we describe a novel Hsp90 client - the intracellular tyrosine kinase, Fer, which is subjected to a unique regulatory regime by this chaperone. Inhibition of Hsp90 activity led to proteasomal degradation of the Fer enzyme.

Novel involvement of the immunomodulator AS101 in IL-10 signaling, via the tyrosine kinase Fer.

Interleukin-10 (IL-10) plays a major proliferative role in many tumors, and activates the transcription factor Stat3 by tyrosine phosphorylation. The immunomodulator ammonium trichloro (dioxoethylene-o,o') tellurate (AS101) has a direct antitumor activity, and is able to sensitize several tumors to chemotherapy, by inhibiting the tumor IL-10 autocrine loop. The tyrosine kinase Fer is essential for the proliferation of numerous malignant cell lines and in some cases was related to Stat3 activation.

trnp: A conserved mammalian gene encoding a nuclear protein that accelerates cell-cycle progression.

We herein describe a novel protein encoded by a single exon in a single-copy conserved mammalian gene. This protein, termed TMF regulated nuclear protein (TRNP), was identified in a yeast "two-hybrid" screen in which the "BC box" containing protein-TMF/ARA160 served as a bait. TRNP is a basic protein which accumulates in an insoluble nuclear fraction in mammalian cells.

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

Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase.

Fer kinase sustains the activation level of ERK1/2 and increases the production of VEGF in hypoxic cells.

Fer is a nuclear and cytoplasmic tyrosine kinase that is ubiquitously expressed in mammalian cells. Herein we show that Fer sustains a key signaling step in hypoxic cells. Knock-down of the Fer protein using a specific siRNA decreased the production of VEGF by the hypoxic cells.

TMF/ARA160 is a BC-box-containing protein that mediates the degradation of Stat3.

TMF/ARA160 is a Golgi resident protein whose cellular functions have not been conclusively revealed. Herein we show that TMF/ARA160 can direct the proteasomal degradation of the key cell growth regulator - Stat3. TMF/ARA160 was dispersed in the cytoplasm of myogenic C2C12 cells that were grown under low-serum conditions.

Fer is a downstream effector of insulin and mediates the activation of signal transducer and activator of transcription 3 in myogenic cells.

Fer is an intracellular tyrosine kinase that associates with signal transducer and activator of transcription 3 (Stat3) in mammalian cells. However, the signaling pathways in which this interaction plays a functional role have not been revealed. Herein, we show that insulin up-regulates the levels of the fer mRNA and Fer protein in myoblasts that undergo insulin-induced myogenic differentiation.

FER kinase activation of Stat3 is determined by the N-terminal sequence.

p94(fer) and p51(ferT) are two tyrosine kinases that share identical SH2 and kinase domains but differ in their N-terminal regions. To further explore the cellular functions of these two highly related tyrosine kinases, their subcellular distribution profiles and in vivo phosphorylation activity were followed using double immunofluorescence assay. When combined with immunoprecipitation analysis, this assay showed that p94(fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2.

Role of positive and negative regulation in modulation of the Fer promoter activity.

p94(fer) is a cytoplasmic and nuclear tyrosine kinase whose function has been linked to cell growth. p94(fer) accumulates at different levels in various cell types and is not detected in pre-B, pre-T and T-cells (Halachmy, S., Bern, O.

Association of yeast SIN1 with the tetratrico peptide repeats of CDC23.

The yeast SIN1 protein is a nuclear protein that together with other proteins behaves as a transcriptional repressor of a family of genes. In addition, sin1 mutants are defective in proper mitotic chromosome segregation. In an effort to understand the basis for these phenotypes, we employed the yeast two-hybrid system to identify proteins that interact with SIN1 in vivo.