| 1995 |
FER kinase constitutively associates with pp120 (p120 catenin) through a ~400 amino acid coiled-coil sequence in its amino terminus; growth factor (EGF, PDGF) stimulation induces phosphorylation of FER and associated pp120 and growth factor receptors. |
Co-immunoprecipitation, in vitro oligomerization assay, growth factor stimulation of A431 cells and 3T3 fibroblasts |
Molecular and cellular biology |
High |
7623846
|
| 1998 |
FER kinase directly binds cortactin through its SH2 domain, and FER kinase activity is required for growth factor-dependent phosphorylation of cortactin; a dominant-negative FER mutant blocks this phosphorylation. |
Co-immunoprecipitation, subcellular fractionation, dominant-negative mutant expression, in vitro kinase assay |
The Journal of biological chemistry |
High |
9722593
|
| 1991 |
FER protein is present in both the cytoplasm and nucleus, where it associates with the chromatin fraction. |
Subcellular fractionation, immunofluorescence |
Molecular and cellular biology |
Medium |
1990274
|
| 1998 |
Overexpression of FER in embryonic fibroblasts induces cell rounding and detachment from substratum, coincident with increased FER–p120(cas) complex formation, tyrosine phosphorylation of p120(cas) and β-catenin, and dissolution of E-cadherin/α-catenin/β-catenin adherens junction complexes. |
Tetracycline-regulatable overexpression system, co-immunoprecipitation, phosphotyrosine Western blotting |
Molecular and cellular biology |
High |
9742093
|
| 1999 |
FER forms trimers in vivo via cooperative interaction of its first and second coiled-coil domains; disruption of either domain abolishes oligomerization. Oligomerization potentiates autophosphorylation in trans at three major sites, but is not required for kinase activation. The testis-specific FerT isoform does not oligomerize. |
Gel filtration, co-immunoprecipitation, in vitro kinase assay with deletion mutants |
The Journal of biological chemistry |
High |
10391941
|
| 1999 |
Mutation of the conserved aspartate (D743R) in subdomain IX of FER's kinase domain abolishes catalytic activity; structural modeling indicates this is due to van der Waals repulsion disrupting the catalytic loop. |
Active-site mutagenesis, in vitro kinase assay in mammalian cells and bacteria, structural modeling |
Protein engineering |
High |
10195287
|
| 2000 |
FER is a downstream target of Fyn kinase in the osmotic stress response: cell shrinkage activates FER in a Fyn-dependent (but Src-independent) manner, and activated FER phosphorylates cortactin at tyrosines 421, 466, and 482. FER also mediates Fyn-dependent phosphorylation of β-catenin, α-catenin, and p120(Cas) upon shrinkage, causing dissociation of β-catenin from cell-cell contacts. |
Kinase activity assays, Fyn/Src-deficient MEFs, site-directed mutagenesis of cortactin tyrosines, co-immunoprecipitation, Src family inhibitor PP2 |
The Journal of biological chemistry |
High |
10921917
|
| 2000 |
FER mediates cross-talk between N-cadherin and β1-integrins: displacement of FER from the N-cadherin juxtamembrane complex (by a competing peptide) causes FER to relocate to the β1-integrin complex, inhibiting both N-cadherin and β1-integrin function. A peptide matching FER's first coiled-coil domain prevents FER accumulation in the integrin complex. |
Trojan peptide competition in cells and tissues, co-immunoprecipitation, cadherin- and integrin-mediated adhesion assays, neurite outgrowth assay |
The Journal of cell biology |
Medium |
10851023
|
| 2000 |
p94(fer) (but not p51(ferT)) activates STAT3 by direct tyrosine phosphorylation; endogenous STAT3 and p94(fer) co-immunoprecipitate. The ability to activate STAT3 is determined by the N-terminal sequence of p94(fer), not by its SH2/kinase domains shared with FerT. |
Co-immunoprecipitation, double immunofluorescence, in vivo phosphorylation assay, chimeric kinase swapping of N-terminal sequences |
The Journal of biological chemistry |
High |
10878010
|
| 2000 |
N-terminal coiled-coil domains of p94(fer) direct oligomerization and autophosphorylation in trans in vivo; the unique N-terminal 43-aa of p51(ferT) prevents its autophosphorylation. The N-terminal tail of p94(fer) expressed ectopically acts as a dominant negative and increases the G0/G1 fraction. |
In vivo autophosphorylation assays, N-terminal deletion and chimeric mutants, cell cycle analysis |
Biochemistry |
Medium |
10998246
|
| 2001 |
Mice homozygous for kinase-inactivating Fer(D743R) mutation are viable and fertile; cortactin phosphorylation is specifically reduced in PDGF-stimulated fer(D743R) MEFs, while phosphorylation of STAT3, p120(ctn), and β-catenin is unaffected, establishing cortactin as a specific Fer substrate in vivo. |
Knock-in mouse model, Western blotting of phospho-substrates in MEFs, PDGF/EGF stimulation |
Molecular and cellular biology |
High |
11134346
|
| 2001 |
Fer kinase is diffusely cytoplasmic (not nuclear) throughout the cell cycle when tracked by GFP fusion and confocal microscopy, in contrast to earlier fractionation reports. |
GFP fusion, confocal fluorescence microscopy, cell cycle synchronization |
Experimental cell research |
Medium |
11339827
|
| 2002 |
Fer kinase is activated downstream of FcεRI aggregation in mast cells and is required for sustained (not initial) p38 MAPK activation; Fer-deficient mast cells show increased adhesion and decreased migration upon FcεRI/Kit activation. |
Bone marrow-derived mast cells from fer(DR/DR) knock-in mice, kinase activity assay, p38/ERK phosphorylation Western blotting, degranulation and migration assays |
Molecular and cellular biology |
High |
12192036
|
| 2002 |
Plectin directly binds the N-terminal domain (aa 1–329) of Fer kinase; this interaction negatively regulates Fer catalytic activity, as Fer is hyperphosphorylated and hyperactive in plectin-null fibroblasts. |
Recombinant protein pulldown, co-immunoprecipitation from fibroblast lysates, immunocomplex kinase assay in plectin-null vs wild-type cells |
Biochemical and biophysical research communications |
Medium |
12200133
|
| 2003 |
Fer phosphorylates β-catenin at Tyr-142 in vitro, disrupting the β-catenin–α-catenin interaction; in K-ras–expressing cells, Fer is activated and Tyr-142 phosphorylation is increased. Fer is constitutively bound to p120 catenin, which acts as a docking protein facilitating Fer activation by Yes kinase. |
In vitro kinase assay, stable K-ras transfectants, co-immunoprecipitation, phosphospecific antibodies |
Molecular and cellular biology |
High |
12640114
|
| 2003 |
Fer kinase phosphorylates PECAM-1 at its ITIM motif and at Tyr-700; Fer is localized on growing microtubules in vascular endothelial cells where it co-localizes with p120 catenin at nascent cell-cell contacts, and a kinase-dead Fer mutant blocks PECAM-1 phosphorylation upon homophilic engagement. |
Expression cloning screen, in vitro kinase assay, dominant-negative mutant, GFP-Fer live-cell time-lapse microscopy |
Molecular biology of the cell |
High |
12972546
|
| 2003 |
Fer kinase associates with N-cadherin, γ-catenin, p120ctn, c-Src, Rab8, actin, and vimentin (but not E-cadherin, afadin, nectin-3, or integrin β1) in the testis, linking it specifically to N-cadherin/catenin-based adherens junctions and intermediate filament structures. |
Co-immunoprecipitation from testis/Sertoli cell lysates, immunohistochemistry with stage-specific localization |
Biology of reproduction |
Medium |
12700184
|
| 2004 |
Fer phosphorylates PTP1B at Tyr-152, enabling PTP1B to bind the cytoplasmic domain of cadherin and maintain β-catenin in a dephosphorylated state at Tyr-654; Fer interacts with cadherin indirectly through p120ctn. fer(D743R) fibroblasts lose cadherin-associated PTP1B and β-catenin at cell-cell contacts. |
Domain mapping (co-IP of Fer/p120ctn interaction domains), peptide competition in live cells, phospho-site mutant β-catenin rescue, analysis of fer(D743R) knock-in MEFs |
Journal of cell science |
High |
15226396
|
| 2004 |
Actin depolymerization (by latrunculin B) promotes Fer–cortactin association and Fer-mediated phosphorylation of cortactin C-terminal tyrosines; the N-terminal actin-binding domain of cortactin is required for efficient association with Fer and for phosphorylation of C-terminal tyrosines. This process is Fyn/Fer-dependent and Src/Abl-independent. |
Latrunculin B/jasplakinolide treatment, candidate kinase-deficient cell lines, co-immunoprecipitation, phospho-mapping of cortactin deletion mutants |
The Biochemical journal |
High |
15030313
|
| 2005 |
FER phosphorylates N-cadherin-associated cortactin, which promotes N-cadherin immobilization at nascent contacts and strengthens intercellular adhesion; in fer(D743R) fibroblasts, cortactin phosphorylation after N-cadherin ligation is reduced, GFP-N-cadherin mobility is faster (FRAP), and intercellular adhesion strength is halved. |
N-cadherin-coated bead pulldown, FRAP, shear wash-off adhesion assay, fer(D743R) MEFs |
Molecular biology of the cell |
High |
16176974
|
| 2006 |
Fer and Fps/Fes kinases are activated downstream of FcεRI in a Lyn-dependent manner and phosphorylate PECAM-1 ITIMs and Tyr-700; mast cells lacking Fer/Fps show reduced FcεRI-induced PECAM-1 phosphorylation and exaggerated degranulation at low antigen doses. |
Kinase activity assay, in vitro phosphorylation of PECAM-1 C-terminus, ITIM phosphorylation in transfected cells, mast cells from Lyn-null and fer/fps kinase-null mice |
The Journal of biological chemistry |
High |
16731527
|
| 2007 |
Fer mediates cortactin tyrosine phosphorylation downstream of integrin engagement in a ROS-dependent manner; fer(DR/DR) MEFs show reduced fibronectin-induced cortactin phosphorylation and impaired cell migration; ROS scavengers or NADPH oxidase inhibition attenuate Fer and cortactin phosphorylation. |
H2O2 stimulation, fibronectin engagement, fer(DR/DR) and Src/Yes/Fyn-null MEFs, NADPH oxidase inhibitor, wound-healing migration assay |
Molecular and cellular biology |
High |
17606629
|
| 2007 |
Fer kinase is required for Sema3A-induced axon retraction in dorsal root ganglion neurons; Fer phosphorylates tubulin and CRMP2 in vitro; CRMP2 and PlexinA1 inhibit Fer autophosphorylation activity in vitro. DRG neurons from fer-deficient mice show significantly diminished axon retraction to Sema3A. |
fer(DR/DR) knock-in and fps-null DRG neuron cultures, Sema3A retraction assay, in vitro kinase assay (tubulin, CRMP2 substrates), autophosphorylation inhibition assay |
BMC developmental biology |
High |
18053124
|
| 2008 |
Presynaptic Fer depletion prevents localization of active zone constituents and synaptic vesicles and inhibits excitatory synapse formation. Fer operates in a p120ctn→Fer→SHP-2→β-catenin presynaptic pathway; depletion of p120ctn or SHP-2 similarly disrupts synaptic vesicle localization, and active SHP-2 or β-catenin overexpression rescues synapse formation in the absence of Fer. |
Fer shRNA in hippocampal neurons, epistasis rescue experiments with SHP-2 and β-catenin, immunofluorescence for active zone/synaptic vesicle markers, electrophysiology |
The Journal of cell biology |
High |
19047464
|
| 2009 |
Phosphatidic acid (PA) binds to an FX (F-BAR extension) domain in Fer, adjacent to its F-BAR domain, and enhances Fer-mediated phosphorylation of cortactin; Fer overexpression enhances lamellipodia formation and cell migration in a PLD-activity- and PA–FX interaction-dependent manner. |
Lipid-binding assay, identification of FX domain, cortactin phosphorylation assay, lamellipodia imaging, cell migration assay with PLD inhibitor |
Science signaling |
High |
19738202
|
| 2009 |
FER activates STAT3 via the IL-6/gp130 pathway: IL-6 triggers rapid formation of Fer/gp130 and Fer/STAT3 complexes, and FER's SH2 domain mediates interaction with STAT3. Modulating FER expression bidirectionally controls STAT3 phosphorylation, nuclear translocation, and IL-6-mediated prostate cancer cell growth. |
Co-immunoprecipitation (Fer/STAT3, Fer/gp130), siRNA knockdown and overexpression, nuclear fractionation, cell proliferation assay |
Molecular cancer research : MCR |
Medium |
19147545
|
| 2010 |
Neuropilin-1 (NRP1) directly and selectively interacts with FER kinase to transduce Sema3A-induced cortical neuron death and axonal retraction; Fer RNAi attenuates Sema3A-induced neurite retraction and neuronal death, and reduces cerebral ischemia-induced brain damage in vivo. |
Co-immunoprecipitation (NRP1–Fer), Fer siRNA, cortical neuron culture Sema3A assay, mouse focal cerebral ischemia model |
The Journal of biological chemistry |
Medium |
20133938
|
| 2011 |
FER overexpression activates NF-κB through EGF receptor signaling: FER binds EGFR (co-IP), FER overexpression increases EGFR and ERK phosphorylation, and FER-mediated NF-κB activation confers resistance to quinacrine; ERK inhibition or FER knockdown blocks EGF-induced NF-κB activation. |
Insertional mutagenesis screen, cDNA overexpression, co-immunoprecipitation of FER–EGFR, siRNA knockdown, ERK/EGFR phosphorylation Western blotting |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
21518868
|
| 2013 |
FER phosphorylates Vav2 at Tyr-172 downstream of EGFR signaling in lung adenocarcinoma cells, which increases Vav2 GEF activity; FER knockdown reduces Rac-GTP localization to lamellipodia, impairs cell migration and invasion in vitro, and reduces spontaneous metastasis in vivo without affecting tumor growth. |
Stable shRNA knockdown, in vitro Fer–Vav2 phosphorylation assay, Rac-GTP pull-down, invasion assay, subcutaneous tumor/spontaneous metastasis mouse model |
Molecular cancer research : MCR |
High |
23699534
|
| 2013 |
FER associates with the PDGF β-receptor through multiple autophosphorylation sites (Tyr-579, Tyr-581, Tyr-740, Tyr-1021); FER kinase-independently (as an adaptor) promotes PDGF-BB-induced STAT3 phosphorylation (not STAT5, ERK1/2, or Akt), and is required for anchorage-independent growth and in vivo tumor formation. |
Co-immunoprecipitation (Fer–PDGFRβ), siRNA knockdown, kinase-dead Fer expression, STAT3/STAT5/ERK/Akt phosphorylation Western blotting, soft agar colony assay, xenograft |
The Journal of biological chemistry |
High |
23589302
|
| 2014 |
Src and Fer directly associate with LRP6 and phosphorylate it on conserved tyrosine residues adjacent to PPPSPxS motifs, negatively regulating Wnt/β-catenin signaling; MEFs lacking Src and Fer show enhanced Wnt signaling. CK1γ inhibits Fer-induced LRP6 phosphorylation, suggesting a de-repression mechanism. |
cDNA expression screen, co-immunoprecipitation (Fer–LRP6), direct in vitro phosphorylation assay, fer/src-null MEFs (Wnt reporter), epistasis analysis |
EMBO reports |
High |
25391905
|
| 2016 |
FER phosphorylates MET (HGFR) at Tyr-1349 in a HGF-ligand- and MET-autophosphorylation-independent manner; this activates RAC1/PAK1 and promotes a kinase-independent MET scaffolding function leading to GAB1 recruitment and phosphorylation, and specific SHP2-ERK pathway activation, driving ovarian cancer metastasis in vitro and in vivo. |
Co-immunoprecipitation (FER–MET), site-specific phosphorylation assay at MET Tyr-1349, RNAi knockdown of FER, RAC1-GTP pull-down, in vivo ovarian cancer metastasis model |
Genes & development |
High |
27401557
|
| 2016 |
FER kinase is responsible for the capacitation-associated increase in sperm tyrosine phosphorylation: Fer kinase-inactivating knock-in mice (but not Pyk2-null mice) fail to show capacitation-associated tyrosine phosphorylation increases, and their sperm display reduced in vitro fertilization ability. |
Fer kinase-inactivating knock-in mice, Pyk2-null mice, pharmacological inhibitors, Western blotting of tyrosine phosphorylation during capacitation, in vitro fertilization assay |
Development (Cambridge, England) |
High |
27226326
|
| 2017 |
The MAN2A1-FER fusion protein localizes to the Golgi (via MAN2A1 signal peptide), has ~4-fold higher tyrosine kinase activity than wild-type FER, and phosphorylates EGFR at Tyr-88; expression activates BRAF, MEK, and AKT signaling and promotes proliferation, invasion, and tumor growth in vivo. |
RT-PCR in tumor samples, tagged fusion protein expression, Golgi fractionation, in vitro kinase assay, EGFR pY88 detection, xenograft tumor model, knockout in HUH7 cells |
Gastroenterology |
High |
28245430
|
| 2017 |
Fer and FerT associate with the mitochondrial electron transport chain in cancer cells; a Fer/FerT inhibitor (E260) disrupts mitochondrial function, induces energy-consuming autophagy, and causes FER to dissociate from PARP-1, leading to PARP-1 activation, energy crisis, and necrotic death selectively in malignant cells. |
Subcellular fractionation/mitochondrial localization, small-molecule inhibitor E260, co-immunoprecipitation (Fer–PARP-1), ATP assay, mitochondrial morphology imaging, xenograft tumor model |
Nature communications |
Medium |
29038547
|
| 2018 |
FER tyrosine kinase phosphorylates CRMP2 at Tyr-479 and Tyr-499; crystal structures of wild-type and phosphomimetic CRMP2-Y479E show that phosphorylation prevents CRMP2 tetramerization, reducing microtubule bundling activity. FER depletion or sub-therapeutic inhibitor doses increase paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. |
In vitro phosphorylation assay, X-ray crystallography of CRMP2 and CRMP2-Y479E, microtubule bundling assay, siRNA knockdown, xenograft model |
Nature communications |
High |
29396402
|
| 2019 |
YY1 directly binds the FER promoter region to suppress FER transcription; reduced FER downstream leads to decreased formation of the STAT3–MMP2 complex, lower MMP2 expression, and inhibition of pancreatic cancer migration and invasion. |
Luciferase reporter, EMSA, ChIP assay, FER knockdown epistasis, in vivo invasion assay |
Cancer letters |
Medium |
31404611
|
| 2021 |
FER phosphorylates PKCδ at Tyr-374; phospho-Y374-PKCδ prevents RAB5 release from late endosomes, blocking RAB5→RAB7 switching, thereby inhibiting EGFR lysosomal degradation and promoting EGFR recycling to the cell surface. PTPN14 phosphatase reverses this by dephosphorylating pY374-PKCδ. |
In vitro FER kinase assay (PKCδ Y374), phospho-specific antibodies, endosome fractionation, RAB5/RAB7 immunofluorescence, PTPN14 dephosphorylation assay, TNBC patient tissue analysis |
The Journal of cell biology |
High |
33411917
|
| 2022 |
FER engages its kinase domain to associate with the PH and PTB domains of IRS4 and phosphorylates IRS4 at Tyr-779; this phosphorylation recruits PIK3R2/p85β and activates the PI3K-AKT pathway, promoting ovarian cancer cell proliferation in vitro and in vivo. |
Mass spectrometry substrate identification, co-immunoprecipitation (kinase domain–IRS4 PH/PTB), in vitro phosphorylation assay, proximity-based tagging (BioID), phosphorylation-defective mutant rescue, xenograft tumor model |
eLife |
High |
35550247
|
| 1998 |
FER (p94fer) and FerT (p51ferT) phosphorylate the TATA element modulatory factor (TMF) on its carboxy-terminal region in vitro and in vivo; TMF was identified as a FER substrate by yeast two-hybrid screening. |
Yeast two-hybrid screen, in vitro kinase assay, in vivo kinase assay, deletion mapping of TMF carboxy-terminus |
FEBS letters |
Medium |
9742951
|
| 2006 |
Downregulation of Fer by RNAi arrests prostate and breast carcinoma cells at G0/G1. At the molecular level, Fer associates with the pRB phosphatase PP1α (via two PP1-binding motifs in its kinase domain), and Fer levels bidirectionally modulate PP1α activity, controlling pRB phosphorylation state and cell-cycle progression. |
RNAi knockdown, co-immunoprecipitation (Fer–PP1α), PP1α enzymatic activity assay, pRB phosphorylation Western blotting, flow cytometry cell-cycle analysis |
Oncogene |
Medium |
16732323
|
| 2013 |
Fer kinase regulates AR tyrosine phosphorylation at Tyr-223 via its SH2 domain interaction with AR, downstream of IL-6/STAT3 signaling, to drive androgen receptor (AR) transcriptional activation and PSA expression in prostate cancer cells. |
Co-immunoprecipitation (Fer–AR via SH2 domain), phospho-AR Tyr-223 detection, Fer siRNA/overexpression, PSA reporter assay, immunofluorescence co-localization in CRPC tissue |
Molecular and cellular endocrinology |
Medium |
23906537
|
| 2015 |
c-Src directly activates Fer by initiating its autophosphorylation, which is further amplified by Fer oligomerization; activated Fer phosphorylates ezrin at focal adhesion membranes, inducing cell transformation. The Src→Fer→ezrin axis is required for tumorigenesis and invasiveness in c-Src-upregulated cancer cells. |
Co-immunoprecipitation (c-Src–Fer at focal adhesion membranes), in vitro kinase assay (Fer phosphorylation of ezrin), Fer knockdown/overexpression, transformation assay, invasion assay |
Oncogene |
Medium |
25867068
|
| 2000 |
Fer associates with insulin signaling complexes in adipocytes: insulin stimulates association of Fer with IRS-1–PI3-kinase complexes and activates PI3-kinase activity in anti-Fer immunoprecipitates, without stimulating Fer tyrosine phosphorylation; PDGF stimulates Fer recruitment to PDGFR–p85 PI3K complexes with Fer phosphorylation. |
Co-immunoprecipitation from 3T3-L1 adipocytes, PI3K enzymatic activity assay in Fer immunoprecipitates, insulin and PDGF stimulation |
The Journal of biological chemistry |
Medium |
11006284
|