Affinage

SRC

Proto-oncogene tyrosine-protein kinase Src · UniProt P12931

Length
536 aa
Mass
59.8 kDa
Annotated
2026-06-10
100 papers in source corpus 48 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

c-Src is a non-receptor tyrosine kinase that transduces signals from membrane receptors and adhesion structures to control cell migration, proliferation, metabolism, and bone remodeling (PMID:8981371, PMID:9331427, PMID:28054552). Its catalytic output is held in check by an intramolecular clamp: the SH2 domain binds the Csk-phosphorylated C-terminal tail at pTyr527, and a competing phosphopeptide that occupies the SH2 domain releases and activates the enzyme (PMID:7683128, PMID:1383688). Activation is consolidated by autophosphorylation of Tyr416 in the activation loop, which rigidifies the kinase domain and detaches the regulatory SH2/SH3 modules to lock in the active conformation and raise activity ~4-fold (PMID:31331936). The freed SH2/SH3 surfaces serve as docking sites that integrate diverse inputs and are themselves required for productive signaling: p130CAS engages both domains to stimulate kinase activity, PKCα drives AFAP-110 onto the SH3 domain to trigger podosome formation, VEGFR2-bound TSAd recruits Src through its SH2 domain, and RACK1 engages the SH2 domain at Lys152 (PMID:10913170, PMID:15314167, PMID:22689825, PMID:31358728). Through these complexes c-Src governs the actin cytoskeleton — controlling podosome dynamics, cortactin/paxillin/p130CAS phosphorylation, and migration downstream of integrins, cadherins, and growth factor receptors (PMID:10913170, PMID:17978100, PMID:9331427, PMID:18482983). In the osteoclast it is essential for cell spreading, podosome turnover, vesicular acidification, and bone resorption, signaling through c-Cbl, the αvβ3/Syk/ITAM module, RACK1, and CLIC-5b, while paradoxically restraining osteoblast differentiation (PMID:8981371, PMID:8849724, PMID:11038178, PMID:17978100, PMID:17353363, PMID:31358728, PMID:16831863). c-Src also phosphorylates and activates an array of receptor and effector substrates — EGFR at Tyr845, the ErbB2 region around Tyr877, connexin-43 at Tyr265 (displacing ZO-1 and closing gap junctions), and FOXM1 in a proliferative feedback loop — and it reciprocally inhibits APC/C-Cdh1 by phosphorylating Cdh1 (PMID:7488034, PMID:11035005, PMID:36795481, PMID:19704002, PMID:31420536). A prominent metabolic function emerges from its direct phosphorylation of glycolytic and pentose-phosphate enzymes (HK1/HK2 at Tyr732, PFKFB3 at Tyr194, G6PD at Tyr112) and mitochondrial complexes (cytochrome c oxidase, NDUFV2 at Tyr193, SDHA at Tyr215), coupling Src activity to glycolysis, oxidative phosphorylation, and tumor growth (PMID:12615910, PMID:22823520, PMID:28054552, PMID:32209481, PMID:33686238). The mutations distinguishing v-Src from c-Src are required for full transformation, underscoring the tight physiological control of this oncogene (PMID:6594680).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1984 High

    Established that wild-type c-Src is not by itself fully transforming, defining the difference between proto-oncogene and viral oncogene and motivating the search for c-Src's intrinsic regulation.

    Evidence NIH 3T3 transfection with focus and soft-agar assays comparing c-Src overexpression to v-Src

    PMID:6594680

    Open questions at the time
    • Did not define the regulatory mechanism keeping c-Src inactive
    • Did not identify the specific activating lesions in v-Src
  2. 1988 High

    Showed that c-Src is enriched and catalytically active in a defined subcellular compartment (neuronal growth cone membranes), linking the kinase to membrane-localized developmental signaling.

    Evidence Subcellular fractionation, immunofluorescence, and in vitro kinase assay in developing rat/chick brain

    PMID:2455889

    Open questions at the time
    • No substrates in the growth cone identified
    • Functional consequence for neuronal development not tested
  3. 1992 High

    Identified Csk-mediated phosphorylation of Tyr527 as the in vivo brake on c-Src, resolving how the kinase is held inactive in cells.

    Evidence Cotransfection/overexpression with Y527F point mutant, kinase and transformation assays

    PMID:1383688

    Open questions at the time
    • Did not show the structural mechanism by which pTyr527 inhibits
    • Physiological signals controlling Csk activity not addressed
  4. 1993 High

    Defined the molecular basis of autoinhibition: the SH2 domain binds pTyr527 intramolecularly, and competition for the SH2 domain releases activity.

    Evidence In vitro GST-SH2 pulldowns with synthetic phosphopeptides and competition kinase assays

    PMID:7683128

    Open questions at the time
    • SH3-linker contribution not resolved in this study
    • Did not address activation-loop autophosphorylation
  5. 1996 High

    Placed c-Src in osteoclast biology, showing it is activated downstream of CSF-1 and required for cell spreading, and identified c-Cbl as a downstream effector for bone resorption.

    Evidence src-null osteoclasts, IP kinase assays, antisense knockdown of src/cbl, confocal colocalization, in vitro resorption assay

    PMID:8849724 PMID:8981371

    Open questions at the time
    • Direct phosphorylation of c-Cbl by c-Src not formally shown
    • Substrate(s) mediating spreading defect incompletely defined
  6. 1995 Medium

    Demonstrated that c-Src directly phosphorylates receptor tyrosine kinase substrates, identifying EGFR Tyr845 within the Src-EGFR complex.

    Evidence In vitro kinase assay on CNBr fragments and phosphopeptide mapping with EGF stimulation

    PMID:7488034

    Open questions at the time
    • Single-lab in vitro result
    • Cellular consequence of Y845 phosphorylation not established here
  7. 2000 High

    Showed c-Src closes gap junctions by phosphorylating connexin-43 Tyr265, which then binds the Src SH2 domain and displaces ZO-1, and that scaffold partners (p130CAS) bidirectionally regulate Src activity.

    Evidence Reconstitution with recombinant proteins, electrophysiology, biotinylation, Y265 mutagenesis; reciprocal co-IP and point mutants for CAS

    PMID:10913170 PMID:11035005

    Open questions at the time
    • Whether these mechanisms operate in the same physiological context not addressed
    • Connexin-43 turnover pathway not fully mapped
  8. 2000 High

    Revealed a negative role for c-Src in osteoblast differentiation, establishing that Src oppositely regulates the two bone cell lineages.

    Evidence src-null mice, bone histomorphometry, antisense knockdown, RT-PCR of differentiation markers

    PMID:11038178

    Open questions at the time
    • Direct Src substrates restraining osteoblast genes not identified
    • Cell-autonomy versus osteoclast crosstalk not fully separated
  9. 2003 High

    Established a mitochondrial localization and function for c-Src, showing it phosphorylates and activates cytochrome c oxidase to support osteoclast bioenergetics.

    Evidence Mitochondrial fractionation, kinase assay, Src knockout/rescue, Cox activity assay

    PMID:12615910

    Open questions at the time
    • Precise Cox phosphosite not defined in this study
    • How Src is imported/retained at mitochondria unclear
  10. 2007 High

    Defined how c-Src organizes the osteoclast cytoskeleton, showing both kinase activity and an intact SH2 or SH3 domain are needed for podosome dynamics, and that Src nucleates an αvβ3/Syk/ITAM complex for resorption.

    Evidence src-null osteoclasts with FRAP/videomicroscopy and domain-mutant rescue; Syk-null mice with co-IP and resorption assays

    PMID:17353363 PMID:17978100

    Open questions at the time
    • Direct Src phosphosites on cytoskeletal components in osteoclasts not enumerated
    • Quantitative coupling of complex assembly to actin flux incomplete
  11. 2012 High

    Connected c-Src to receptor-proximal scaffolds and a proliferative transcription program: TSAd links VEGFR2 to Src for vascular permeability, and Src phosphorylates FOXM1 to drive a feed-forward proliferation loop.

    Evidence TSAd knockout mice with reciprocal co-IP and permeability assays; Src-deletion mouse model with FOXM1 phosphosite mapping and target gene readouts

    PMID:22689825 PMID:36795481

    Open questions at the time
    • FOXM1 tyrosine sites only partially characterized
    • Generality of TSAd-Src axis beyond endothelium not addressed
  12. 2012 High

    Extended Src's mitochondrial reach to electron transport chain subunits, distinguishing activating (NDUFV2 Y193) from ROS-inducing (SDHA Y215) phosphorylation events tied to cell viability.

    Evidence Mitochondria-targeted kinase-dead Src construct, phosphosite mutants, enzyme activity and ROS assays

    PMID:22823520

    Open questions at the time
    • Endogenous mitochondrial Src activity regulation unclear
    • Physiological versus pathological balance of complex I/II phosphorylation not resolved
  13. 2019 High

    Resolved the structural logic of activation, showing Tyr416 autophosphorylation rigidifies the kinase domain and frees the regulatory domains to lock the active state.

    Evidence Hydrogen/deuterium exchange MS with kinase assays and molecular dynamics

    PMID:31331936

    Open questions at the time
    • Kinetics of the regulatory-domain release in cells not measured
    • Interplay with pTyr527 dephosphorylation not directly tested here
  14. 2019 Medium

    Showed c-Src feeds back on cell-cycle machinery and chromatin/EMT regulators, phosphorylating Cdh1 to inhibit APC/C-Cdh1, HDAC3 to enhance deacetylase activity and invasion, and E-cadherin to trigger its degradation and β-catenin nuclear translocation.

    Evidence Reciprocal co-IP and kinase/E3 ligase assays (Cdh1); in vitro kinase with phosphosite mutants and invasion assay (HDAC3); ubiquitination assay with phosphosite mutants (E-cadherin)

    PMID:31286874 PMID:31420536 PMID:31430896

    Open questions at the time
    • HDAC3 and E-cadherin findings rest on single-lab data
    • In vivo relevance of the Src-Cdh1 circuit in normal cycling cells not established
  15. 2021 High

    Consolidated c-Src as a master kinase of cancer metabolism by direct phosphorylation of glycolytic and pentose-phosphate enzymes (HK1/HK2 Y732, PFKFB3 Y194, G6PD Y112) that boost flux and tumorigenesis, validated in knockin mouse models.

    Evidence In vitro kinase assays with enzyme kinetics, phosphosite knockin mice, metabolic flux and tumor models, clinical correlation

    PMID:28054552 PMID:32209481 PMID:33686238

    Open questions at the time
    • Upstream signals directing Src to metabolic enzymes not fully defined
    • Subcellular site of these phosphorylation events not pinpointed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple c-Src-regulating scaffolds and inhibitory partners (RACK1, MPP2, MerTK/STAT3, connexin-43/PTEN/Csk) are integrated to set Src activity in a given cell, and how its membrane/mitochondrial/nuclear substrate pools are spatially partitioned, remains unresolved.
  • No unified model linking compartment-specific Src pools to distinct substrate sets
  • Quantitative hierarchy among competing positive and negative regulators not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 2 GO:0005856 cytoskeleton 2 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-1500931 Cell-Cell communication 2 R-HSA-1640170 Cell Cycle 2
Partners
AFAP-110C-CBLCSKFAKP130CASRACK1SYKTSAD
Complex memberships
MerTK–c-Src–STAT3–PI3K complexVEGFR2–TSAd–c-Src complexαvβ3 integrin–Syk–c-Src complex

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The c-Src SH2 domain binds directly to the phosphorylated C-terminal tail (pTyr527) of c-Src in vitro, and this intramolecular interaction maintains c-Src in an inactive conformation. A competing phosphopeptide that binds the SH2 domain activates c-Src kinase activity in vitro, and this activation is blocked by excess purified SH2 domain. In vitro GST-SH2 domain pulldown with synthetic phosphopeptides, competition kinase assays Oncogene High 7683128
1992 C-terminal Src kinase (Csk) suppresses c-Src kinase activity in vivo by phosphorylating Tyr527; overexpression of Csk reverses v-Crk-induced c-Src activation and cellular transformation, and this suppression is abolished when Tyr527 is mutated to Phe. Cotransfection/overexpression, kinase activity assay, morphological transformation assay Molecular and cellular biology High 1383688
1996 c-Src is required for osteoclast spreading downstream of CSF-1 receptor (c-Fms); c-Src is tyrosine-phosphorylated and its kinase activity increases ~3-fold upon CSF-1 stimulation, and src-null osteoclasts fail to spread and show altered downstream substrate phosphorylation (including alpha-actinin). Immunoprecipitation kinase assay, src-null mouse osteoclasts, confocal microscopy, Western blot Molecular reproduction and development High 8981371
1996 c-Cbl is tyrosine-phosphorylated in a c-Src-dependent manner in osteoclasts; c-Cbl and c-Src colocalize on vesicular structures; antisense knockdown of either c-src or c-cbl inhibits in vitro bone resorption, placing c-Cbl downstream of c-Src in a signaling pathway required for bone resorption. Antisense oligonucleotides, immunoprecipitation/phosphorylation assay, src-null osteoclasts, confocal colocalization, in vitro bone resorption assay Nature High 8849724
1988 pp60c-Src is concentrated at least 9-fold in nerve growth cone membrane fractions of developing rat brain and is an active tyrosine kinase in that compartment, with altered electrophoretic mobility characteristic of the neuronal form; it is present at lower levels in mature brain synaptosomal fractions. Subcellular fractionation, indirect immunofluorescence, in vitro kinase assay Proceedings of the National Academy of Sciences of the United States of America High 2455889
1984 Overexpression of wild-type c-Src in NIH 3T3 cells elevates tyrosine kinase activity and causes partial morphological transformation but does not induce foci or anchorage-independent growth, demonstrating that the mutations distinguishing v-Src from c-Src are required for full transformation. NIH 3T3 transfection/focus assay, soft-agar colony assay, in vitro kinase assay Proceedings of the National Academy of Sciences of the United States of America High 6594680
1995 c-Src directly phosphorylates the EGF receptor at Tyr845 within the c-Src–EGFR complex in an EGF-dependent manner, as demonstrated by in vitro kinase assay on cyanogen bromide fragments and phosphopeptide mapping co-migration with a synthetic pTyr845 standard. In vitro kinase assay, cyanogen bromide fragment phosphorylation, phosphopeptide mapping, in-cell EGF stimulation Biochemical and biophysical research communications Medium 7488034
2000 Constitutively active c-Src phosphorylates connexin-43 at Tyr265, causing the phosphorylated C-terminus to bind the c-Src SH2 domain and displacing ZO-1; this reduces total and surface connexin-43 levels and diminishes gap junctional conductance. A Tyr265 mutant connexin-43 retains ZO-1 interaction despite active c-Src. Cotransfection, in vitro binding assay with recombinant proteins, cell-surface biotinylation, electrophysiology, site-directed mutagenesis The Journal of biological chemistry High 11035005
2000 Deletion/reduction of c-Src expression in mice enhances osteoblast differentiation and bone formation, increases alkaline phosphatase activity, nodule mineralization, and upregulates osteoblast differentiation markers (Osf2/Cbfa1, osteocalcin, collagen) in vitro and in vivo, demonstrating a negative regulatory role of c-Src in osteoblastogenesis. Src-null mice, bone histomorphometry, antisense oligonucleotide knockdown in primary osteoblasts, RT-PCR, in vitro differentiation assays The Journal of cell biology High 11038178
2003 c-Src localizes to mitochondria in osteoclasts and phosphorylates cytochrome c oxidase (Cox), increasing its enzymatic activity. Src deletion reduces Cox activity; re-expression of c-Src restores it. Increasing Src kinase activity reverses calcitonin-mediated inhibition of Cox and osteoclast function. Mitochondrial fractionation, kinase assay, c-Src knockout/rescue with adenoviral vectors, Cox activity assay The Journal of cell biology High 12615910
2000 p130CAS (CAS) binds directly to both the SH2 and SH3 domains of c-Src and activates its tyrosine kinase activity; a single amino acid substitution in the CAS SH3-binding site disrupts both CAS–c-Src interaction and c-Src-dependent phosphorylation of cortactin and paxillin. Co-immunoprecipitation, overexpression in COS-1 cells, site-directed mutagenesis, tyrosine phosphorylation assay, soft-agar growth assay Molecular and cellular biology High 10913170
2003 PLD2 (and to a lesser extent PLD1) are directly tyrosine-phosphorylated by c-Src via direct association; the interaction is mediated by the PLD2 pleckstrin homology domain and the c-Src catalytic domain. PLD catalytic activity (but not c-Src phosphorylation of PLD) in turn stimulates c-Src kinase activity and c-Src-mediated paxillin phosphorylation. Co-immunoprecipitation, in vitro kinase assay, domain-mapping mutagenesis, EGF stimulation in A431 cells Molecular and cellular biology Medium 12697812
2004 PKCα activates c-Src via the scaffold protein AFAP-110: PKCα activation directs AFAP-110 to bind the c-Src SH3 domain, which activates c-Src kinase activity and promotes podosome formation containing cortactin, AFAP-110, actin, and c-Src. Cells lacking AFAP-110 cannot undergo PKCα-mediated c-Src activation or podosome formation, and rescue requires AFAP-110 capable of binding c-Src. Immunofluorescence, co-immunoprecipitation, kinase assay, AFAP-110-deficient cell line rescue, site-directed mutagenesis of AFAP-110 Molecular and cellular biology High 15314167
2007 c-Src regulates podosome formation, structure, life span, and actin flux in osteoclasts; Src−/− osteoclasts show fewer podosomes, decreased actin cloud, 4-fold increased podosome lifespan, and 40% reduced actin flux rate. Rescue with Src mutants shows both kinase activity AND either the SH2 or SH3 binding domain are required for normal podosome dynamics. Src-null osteoclasts, videomicroscopy, FRAP, adenoviral rescue with c-Src kinase/domain mutants, fluorescence microscopy Molecular biology of the cell High 17978100
2007 c-Src forms an essential signaling complex with αvβ3 integrin and Syk in osteoclasts; upon integrin activation, c-Src phosphorylates Syk, and ITAM proteins Dap12 and FcRγ mediate the Syk–c-Src association and αvβ3-induced Syk phosphorylation required for cytoskeletal organization and bone resorption. Syk-null mice (in vitro and chimeric in vivo), co-immunoprecipitation, kinase assay, cytoskeletal staining, bone resorption assay The Journal of cell biology High 17353363
2012 VEGFR2 phosphorylated at Y951 binds the SH2 domain of TSAd, which in turn recruits and activates c-Src (increased pY418, decreased pY527); TSAd silencing blocks VEGF-induced c-Src activation and VE-cadherin junction rearrangement. TSAd, VEGFR2, and c-Src form a complex at endothelial junctions, and Tsad−/− mice show impaired VEGF-induced vascular permeability. TSAd knockout mice, siRNA silencing, co-immunoprecipitation, phosphorylation assays, Evans blue/dextran permeability assay, in vitro and in vivo experiments The Journal of experimental medicine High 22689825
2012 c-Src phosphorylates mitochondrial NADH dehydrogenase subunit NDUFV2 at Tyr193 (required for NADH dehydrogenase/complex I activity and cellular ATP) and SDHA at Tyr215 (no effect on enzyme activity but induces ROS via electron transfer perturbation); phosphorylation-defective mutants reduce cell viability. Mitochondrial kinase-dead c-Src with targeting sequence, phosphorylation-site mutagenesis, enzymatic activity assays, ROS measurement, cell viability assay The Biochemical journal High 22823520
2012 c-Src phosphorylates FOXM1 on two tyrosine residues, stimulating FOXM1 nuclear localization and target gene expression (including G2/M regulators and c-Src itself), forming a positive feedback loop that drives mammary tumor cell proliferation. Genetically engineered mouse model with c-Src deletion, phosphorylation mapping, nuclear localization assay, target gene expression, patient-derived models The Journal of clinical investigation High 36795481
1995 c-Src associates with the prolactin receptor in rat hepatocytes and is activated upon prolactin stimulation, as shown by co-immunoprecipitation; prolactin treatment also induces c-src, c-fos, and c-jun gene expression. Co-immunoprecipitation kinase assay from hepatocyte lysates, Western blot Molecular endocrinology Medium 8584023
2000 c-Src stimulation by prolactin is independent of Jak2: a Box1-mutant PRLR that cannot activate Jak2 (and thus cannot phosphorylate the receptor) still activates c-Src equivalently to wild-type PRLR upon prolactin treatment. Expression of Box1-mutant PRLR and kinase-deleted Jak2 in chicken embryo fibroblasts, c-Src kinase activity assay The Biochemical journal Medium 10600634
2003 EphB1 recruits c-Src and p52Shc; activated EphB1 promotes c-Src tyrosine phosphorylation, and c-Src phosphorylates p52Shc, enabling p52Shc recruitment to EphB1 signaling complexes via its PTB domain. EphB1 tyrosines 600 and 778 are required for c-Src and p52Shc interaction. Dominant-negative c-Src reduces ERK1/2 activation and chemotaxis. Co-immunoprecipitation, site-directed mutagenesis of EphB1, dominant-negative c-Src expression, MEK inhibitor, ERK assay, migration assay The Journal of cell biology High 12925710
1997 c-Src is required downstream of the PDGF and EGF receptors for mitogenesis; preferred c-Src substrates include cortactin, p190RhoGAP, and p130CAS (actin cytoskeleton/focal adhesion proteins), while EGF receptor substrates include SHC and PLCγ. C3H10T fibroblast model with wild-type and mutant c-Src, substrate phosphorylation comparison, temporal/spatial signaling analysis Frontiers in bioscience Medium 9331427
1997 c-Src activates both STAT1 and STAT3 in PDGF-stimulated NIH3T3 cells; STAT1 co-immunoprecipitates with c-Src, suggesting direct interaction; overexpression of dominant-negative c-Src reduces STAT1/3 tyrosine phosphorylation and DNA binding activity. Co-immunoprecipitation, overexpression of c-Src and dominant-negative Src, EMSA for DNA binding activity, tyrosine phosphorylation assay Biochemical and biophysical research communications Medium 9344858
2004 Pyk2 and c-Src synergistically activate Stat3 downstream of EGFR; EGF stimulation recruits c-Src, Pyk2, and Stat3 to EGFR; dominant-negative Pyk2 impairs c-Src-induced Stat3 activation; Pyk2 expression induces Stat3 phosphorylation at Tyr705 and Ser727. Co-immunoprecipitation, dominant-negative constructs, luciferase reporter assay, Western blot for phospho-Stat3 The Journal of biological chemistry Medium 14963038
2006 Trans-interacting cadherin locally activates c-Src at cell-cell adhesion sites; c-Src then tyrosine-phosphorylates Vav2 (Rac-GEF) and activates Rap1 via C3G/Crk; both c-Src phosphorylation of Vav2 AND Rap1 activation (via PI3K) are jointly required for Rac activation. Inhibitor studies (PP2), dominant-negative constructs, co-immunoprecipitation, GTPase activity assays, cadherin trans-interaction model in fibroblasts and epithelial cells Oncogene Medium 16170364
2005 Aldosterone activates vascular c-Src through the mineralocorticoid receptor (eplerenone-sensitive); activated c-Src then mediates p38 MAPK phosphorylation and NADPH oxidase activation; c-Src-deficient (c-Src+/−) VSMCs fail to show aldosterone-induced cortactin or p38 MAPK phosphorylation. c-Src heterozygous mouse VSMCs, PP2 inhibitor, eplerenone, kinase assays, Western blot, [3H]proline incorporation Hypertension Medium 15699470
2008 Endosomal NADPH oxidases (Nox1, Nox2) generate ROS that activate c-Src following hypoxia/reoxygenation; Rac1-dependent endocytosis recruits c-Src to endosomes where endosomal ROS activate it; activated c-Src then phosphorylates IκBα on tyrosine to activate NF-κB. Quenching endosomal ROS or Rac1 siRNA blocks c-Src activation. siRNA knockdown (Rac1), Nox-deficient primary fibroblasts, endosomal fractionation, intra-endosomal ROS quenching, phosphorylation assay The Biochemical journal Medium 18397177
2009 c-Src associates with ErbB2 specifically through an interaction involving the ErbB2 kinase domain region surrounding Tyr877 (EGFR(YHAD) motif); this association does not require c-Src SH2 or SH3 domains or receptor phosphorylation, and confers enhanced transforming potential. EGFR mutants found in lung cancer that gain the Y877 equivalent motif also bind c-Src. Chimeric EGFR/ErbB2 receptors, co-immunoprecipitation, site-directed mutagenesis, in vitro and in vivo transformation assays, Stat3 activation assay Molecular and cellular biology High 19704002
2006 c-Src overexpression enhances ErbB2/ErbB3 heterocomplex formation and their basal and heregulin-induced activation; kinase-inactive c-Src or PP2 treatment reduces heterocomplex formation and downstream signaling, indicating c-Src acts upstream to positively modulate ErbB2/ErbB3 association. Co-immunoprecipitation, wild-type vs. kinase-inactive c-Src overexpression, PP2 pharmacological inhibition, receptor activation Western blot, migration and anchorage-independent growth assays Oncogene Medium 17173075
2017 c-Src directly phosphorylates hexokinase 1 (HK1) at Tyr732 and HK2, dramatically increasing their catalytic activity (decreased Km, increased Vmax for HK1) by disrupting HK1 dimer formation. HK1-Y732F or HK2 phosphosite mutants abrogate c-Src-stimulated glycolysis, cell proliferation, tumorigenesis, and metastasis. In vitro kinase assay, Km/Vmax measurements, site-directed mutagenesis (Y732F knockin and knockin mice), xenograft and metastasis models, clinical sample correlation Nature communications High 28054552
2020 c-Src phosphorylates PFKFB3 at Tyr194, activating this key glycolytic enzyme to boost fructose-2,6-bisphosphate production and PFK1 activity, replenishing PPP and serine pathways. PFKFB3-Y194F knockin mice show impaired glycolysis and reduced spontaneous colon cancer formation when crossed with APCmin/+ mice. In vitro kinase assay, site-directed mutagenesis (Y194F), PFKFB3 knockout cells, PFKFB3-Y194F knockin mice, metabolic flux assay, APCmin/+ cross, clinical sample correlation Cell reports High 32209481
2021 c-Src interacts with and phosphorylates G6PD at Tyr112, enhancing its catalytic activity (decreased Km, increased Kcat) for glucose-6-phosphate, thereby augmenting PPP flux for NADPH and ribose-5-phosphate production and promoting tumorigenesis. Co-immunoprecipitation, in vitro kinase assay, enzyme kinetics (Km/Kcat), site-directed mutagenesis (Y112), clinical colorectal cancer sample correlation Oncogene High 33686238
2019 c-Src phosphorylates E-cadherin at Tyr797, triggering RNF43-mediated ubiquitination of E-cadherin at Lys816 and subsequent proteasomal degradation, enabling nuclear β-catenin translocation and EMT in lung adenocarcinoma. Immunoprecipitation, ubiquitination assay, phospho-specific antibody, shRNA knockdown, xenograft model, site-directed mutagenesis BMC cancer Medium 31286874
2019 Cdh1 (APC/C co-activator) suppresses c-Src kinase activity in an APC-independent manner; reciprocally, hyperactive c-Src phosphorylates Cdh1 at its N-terminus, disrupting Cdh1 interaction with the APC core complex and inhibiting APCCdh1 E3 ligase activity, forming a reciprocal feedback circuit. Co-immunoprecipitation, kinase assay, site-directed mutagenesis, ubiquitin E3 ligase assay, mouse mammary tumor model (PTEN loss), pharmacological c-Src inhibition Nature communications High 31420536
2019 RACK1 interacts with c-Src via RACK1 tyrosines 228 and 246 (binding the c-Src SH2 domain at Lys152); RACK1-Y228F/Y246F mutant fails to interact with c-Src and impairs osteoclast cytoskeletal integrity and bone resorption without affecting differentiation. c-Src K152R similarly impairs osteoclast resorption. Co-immunoprecipitation, site-directed mutagenesis of RACK1 and c-Src, osteoclast differentiation/resorption assays, cytoskeletal analysis Experimental & molecular medicine Medium 31358728
2019 c-Src autophosphorylation at Tyr416 causes global structural rearrangements: the kinase domain gains rigidity and stabilizes the ATP-binding site, while the regulatory SH2/SH3 domains become more flexible and detach from the kinase domain, resulting in a 4-fold increase in enzymatic activity. Hydrogen/deuterium exchange MS, biochemical kinase activity assay, molecular dynamics simulations The Journal of biological chemistry High 31331936
2013 Molecular dynamics free-energy calculations demonstrate that phosphorylation of Tyr416 in the activation loop locks c-Src into a catalytically competent conformation by stabilizing the hydrophobic regulatory spine, HRD motif, and electrostatic switch; unphosphorylated A-loop shows high flexibility and the active conformation is only transiently visited. Molecular dynamics umbrella sampling free-energy simulations Journal of molecular biology Low 24103328
2002 Dominant-negative c-Src (K295M) prevents acid-induced activation of NHE3 in renal epithelial cells, placing c-Src upstream of NHE3 in the response to chronic acidosis; acid-induced ERK activation is independent of c-Src, demonstrating two parallel pathways both required for NHE3 activation. Dominant-negative c-Src transfection, NHE3 activity assay (pHi recovery), immune-complex kinase assay, MEK inhibitor (PD98059) Kidney international Medium 12081562
2006 c-Src controls functional co-localization of the proton pump and CLIC-5b chloride channel in osteoclast vesicles, which is required for vesicular acidification and bone resorption. CLIC-5b binds c-Src SH2 and SH3 domains. c-Src suppression reduces vesicular acidification (rescued by valinomycin), consistent with selective loss of chloride conductance. c-Src siRNA knockdown, CLIC-5b siRNA knockdown, vesicular acidification assay, valinomycin rescue, affinity pull-down with Src SH2/SH3 domains, bone resorption assay The Journal of biological chemistry Medium 16831863
2016 Connexin43 recruits PTEN and Csk to its C-terminal region (residues 266–283) to inhibit c-Src; pull-down assays show this region is sufficient to recruit c-Src, PTEN, and Csk and inhibit oncogenic c-Src activity. Silencing Csk or PTEN reduces the antiproliferative effect of Cx43 in glioma cells. Pull-down assays with Cx43 peptide fragments, co-immunoprecipitation, confocal microscopy, siRNA silencing of Csk and PTEN, phosphorylation assays (pY527, pY416) Oncotarget Medium 27391443
2009 Apoptotic cell binding to MerTK on dendritic cells establishes a complex containing MerTK, c-Src, STAT3, and PI3K; this activates c-Src and STAT3 and mediates inhibition of DC maturation. Pharmacological inhibitors or siRNA against c-Src or STAT3 block apoptotic cell-induced DC inhibition. Co-immunoprecipitation, phosphorylation assay, siRNA knockdown, pharmacological inhibitors, MerTK-knockout DCs, DC maturation assay Blood Medium 19667404
2002 c-Src co-immunoprecipitates with c-Cbl and both localize to Golgi-enriched membrane fractions in CHO cells; activated (but not wild-type) c-Src increases the amount of c-Cbl co-immunoprecipitating with Src and the intensity of c-Cbl Golgi staining, with concomitant increased tyrosine phosphorylation of membrane-associated Cbl. Co-immunoprecipitation, subcellular fractionation (density centrifugation and free-flow electrophoresis), confocal immunofluorescence, activated c-Src transfection European journal of cell biology Medium 11893076
2019 c-Src phosphorylates HDAC3 at Tyr328 and Tyr331; phosphorylated HDAC3 shows higher deacetylase activity, is recruited to the plasma membrane upon EGF stimulation, and promotes breast cancer cell invasion. PP2 (c-Src inhibitor) blocks HDAC3 phosphorylation and reduces enzymatic activity. Site-directed mutagenesis (Y328/331A), phospho-specific antibody, in vitro kinase assay, TIRF microscopy, invasion assay, c-Src knockdown Cells Medium 31430896
2021 Inhibitor binding to c-Src induces a conformational change that promotes c-Src association with FAK in an active form; upon inhibitor dissociation, c-Src phosphorylates FAK and initiates FAK-Grb2-Erk signaling. A drug-resistant c-Src mutation that reduces inhibitor affinity paradoxically converts Src inhibitors into facilitators of FAK/Erk phosphorylation and cell proliferation. Co-immunoprecipitation with c-Src inhibitors, phosphorylation assay (FAK, Erk), drug-resistant c-Src mutant cells, cell proliferation assay Cell reports Medium 33761359
2008 c-Src is the specific kinase required for villin-mediated intestinal cell migration; reconstitution of SYF (Src/Yes/Fyn triple-knockout) cells individually with c-Src, c-Yes, or c-Fyn demonstrates an absolute requirement for c-Src specifically. SHP-2 and PTP-PEST are identified as negative regulators of c-Src activity in this context. SYF cells reconstituted with individual kinases, cell migration assay, villin phosphorylation assay, siRNA for phosphatases The Journal of biological chemistry High 18482983
2014 c-Src drives intestinal stem cell (ISC) proliferation, regeneration, and tumorigenesis through upregulation of EGFR and activation of Ras/MAPK and Stat3 signaling, as shown by genetic gain- and loss-of-function in both Drosophila and mouse intestinal epithelium; c-Src plays a non-redundant role that cannot be substituted by Fyn or Yes. Genetic gain- and loss-of-function (Drosophila and conditional mouse knockout), ISC proliferation assay, EGFR/MAPK/Stat3 pathway activation readouts The EMBO journal High 24788409
2012 c-Src stimulates IL-6 expression through STAT3; IL-6 in turn induces IGFBP5, which activates c-Src in immature (but not mature) osteoblasts, creating an amplifying loop that maintains osteoblasts in an immature state; IGFBP5 produced by osteoblasts also stimulates osteoclastogenesis. c-Src inhibition, siRNA knockdown, STAT3 reporter, cytokine measurements, in vitro and in vivo osteoblast/osteoclast assays Nature communications Medium 22252554
2016 The PDZ protein MPP2 interacts with c-Src via its PDZ domain in epithelial cells (identified by PDZ domain array screen and confirmed by co-immunoprecipitation); MPP2 negatively regulates c-Src kinase activity in cells and suppresses c-Src-dependent disorganization of the cortical actin cytoskeleton. PDZ domain array screen, co-immunoprecipitation, kinase activity assay, cytoskeletal imaging Experimental cell research Medium 19665017

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 c-Src and cooperating partners in human cancer. Cancer cell 506 15380511
1996 c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption. Nature 247 8849724
2000 Decreased c-Src expression enhances osteoblast differentiation and bone formation. The Journal of cell biology 236 11038178
2007 Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. The Journal of cell biology 234 17353363
1988 c-src gene product in developing rat brain is enriched in nerve growth cone membranes. Proceedings of the National Academy of Sciences of the United States of America 219 2455889
2005 Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension (Dallas, Tex. : 1979) 211 15699470
2005 High yield bacterial expression of active c-Abl and c-Src tyrosine kinases. Protein science : a publication of the Protein Society 197 16260764
2012 VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd. The Journal of experimental medicine 195 22689825
1993 Regulation of c-Src tyrosine kinase activity by the Src SH2 domain. Oncogene 189 7683128
2003 Regulation of cytochrome c oxidase activity by c-Src in osteoclasts. The Journal of cell biology 184 12615910
2000 c-Src regulates the interaction between connexin-43 and ZO-1 in cardiac myocytes. The Journal of biological chemistry 176 11035005
2007 The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts. Molecular biology of the cell 169 17978100
2004 Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene 164 15489915
1984 Overexpression of the c-src protein does not induce transformation of NIH 3T3 cells. Proceedings of the National Academy of Sciences of the United States of America 153 6594680
1994 Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis. The Journal of clinical investigation 135 7509341
1995 c-Src phosphorylates epidermal growth factor receptor on tyrosine 845. Biochemical and biophysical research communications 122 7488034
2007 c-Src protein kinase inhibitors block assembly and maturation of dengue virus. Proceedings of the National Academy of Sciences of the United States of America 118 17360676
1996 pp60(c-src) is required for cell locomotion regulated by the hyaluronanreceptor RHAMM. Oncogene 117 8950989
2000 Regulation of c-SRC activity and function by the adapter protein CAS. Molecular and cellular biology 113 10913170
2017 c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis. Nature communications 110 28054552
2012 Development of a highly selective c-Src kinase inhibitor. ACS chemical biology 110 22594480
1992 Increased tyrosine kinase activity of c-Src during calcium-induced keratinocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 107 1381508
1992 Activation of c-Src in cells bearing v-Crk and its suppression by Csk. Molecular and cellular biology 106 1383688
2012 c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nature communications 100 22252554
2003 EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. The Journal of cell biology 91 12925710
2010 Invasive prostate carcinoma driven by c-Src and androgen receptor synergy. Cancer research 89 21135112
2003 Transmodulation between phospholipase D and c-Src enhances cell proliferation. Molecular and cellular biology 86 12697812
2004 Protein kinase Calpha activates c-Src and induces podosome formation via AFAP-110. Molecular and cellular biology 85 15314167
2012 Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components. The Biochemical journal 84 22823520
1997 Role of c-Src tyrosine kinase in EGF-induced mitogenesis. Frontiers in bioscience : a journal and virtual library 84 9331427
2006 c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function. Oncogene 82 17173075
1995 Prolactin receptor is associated with c-src kinase in rat liver. Molecular endocrinology (Baltimore, Md.) 82 8584023
2006 The role of c-Src kinase in the regulation of osteoclast function. Modern rheumatology 78 16633924
2006 Role of c-Src in human MCF7 breast cancer cell tumorigenesis. The Journal of biological chemistry 77 16728403
2013 Locking the active conformation of c-Src kinase through the phosphorylation of the activation loop. Journal of molecular biology 72 24103328
2005 c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells. Cellular signalling 71 15494217
2013 c-Src modulates estrogen-induced stress and apoptosis in estrogen-deprived breast cancer cells. Cancer research 68 23704208
2006 Activation of Rac by cadherin through the c-Src-Rap1-phosphatidylinositol 3-kinase-Vav2 pathway. Oncogene 68 16170364
2003 Synergistic promotion of c-Src activation and cell migration by Cas and AND-34/BCAR3. The Journal of biological chemistry 65 12740391
2004 siRNA directed against c-Src enhances pancreatic adenocarcinoma cell gemcitabine chemosensitivity. Journal of the American College of Surgeons 63 15194078
2004 Involvement of c-Src kinase in the regulation of TGF-beta1-induced apoptosis. Oncogene 63 15208664
2014 c-Src drives intestinal regeneration and transformation. The EMBO journal 61 24788409
2020 c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve? Cancers 58 32517369
2010 c-Src differentially regulates the functions of microtentacles and invadopodia. Oncogene 58 20956943
2008 Identification of c-Src tyrosine kinase substrates using mass spectrometry and peptide microarrays. Journal of proteome research 57 18698806
2006 Lipopolysaccharide-induced c-Src expression plays a role in nitric oxide and TNFalpha secretion in macrophages. Molecular immunology 56 15869794
2020 c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3. Cell reports 54 32209481
2018 Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1. Scientific reports 54 30013043
2002 Role of c-SRC and ERK in acid-induced activation of NHE3. Kidney international 54 12081562
1997 c-Src activates both STAT1 and STAT3 in PDGF-stimulated NIH3T3 cells. Biochemical and biophysical research communications 54 9344858
2016 c-Src/Cav1-dependent activation of the EGFR by Dsg2. Oncotarget 53 26918609
1993 The cell cycle and c-Src. Current opinion in genetics & development 53 7680927
2016 Connexin43 recruits PTEN and Csk to inhibit c-Src activity in glioma cells and astrocytes. Oncotarget 52 27391443
2014 c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction. Journal of the American College of Cardiology 52 24361364
2012 Identification of targets of c-Src tyrosine kinase by chemical complementation and phosphoproteomics. Molecular & cellular proteomics : MCP 52 22499769
2011 c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation. American journal of physiology. Cell physiology 51 21508333
2009 c-Src associates with ErbB2 through an interaction between catalytic domains and confers enhanced transforming potential. Molecular and cellular biology 51 19704002
2008 Endosomal NADPH oxidase regulates c-Src activation following hypoxia/reoxygenation injury. The Biochemical journal 51 18397177
2011 Mammary epithelial-specific disruption of c-Src impairs cell cycle progression and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 48 21628573
2000 Involvement of c-Src in diperoxovanadate-induced endothelial cell barrier dysfunction. American journal of physiology. Lung cellular and molecular physiology 45 10956618
1989 c-src and other proto-oncogenes implicated in neuronal differentiation. Molecular and chemical neuropathology 44 2472150
2014 c-Src function is necessary and sufficient for triggering microglial cell activation. Glia 43 25421817
2008 Functional dissection of transformation by c-Src and v-Src. Genes to cells : devoted to molecular & cellular mechanisms 43 18173743
2006 c-Src control of chloride channel support for osteoclast HCl transport and bone resorption. The Journal of biological chemistry 43 16831863
2004 Pyk2 amplifies epidermal growth factor and c-Src-induced Stat3 activation. The Journal of biological chemistry 43 14963038
2010 Elevated c-Src and c-Yes expression in malignant skin cancers. Journal of experimental & clinical cancer research : CR 42 20796316
2023 Role of c-Src in Carcinogenesis and Drug Resistance. Cancers 41 38201459
2005 Novel insights into c-Src. Current pharmaceutical design 41 15853660
2012 HIF-1 and c-Src mediate increased glucose uptake induced by endothelin-1 and connexin43 in astrocytes. PloS one 40 22384254
2008 Potential molecular mechanism for c-Src kinase-mediated regulation of intestinal cell migration. The Journal of biological chemistry 40 18482983
2002 Molecular complexes that contain both c-Cbl and c-Src associate with Golgi membranes. European journal of cell biology 37 11893076
2013 Development of a chimeric c-Src kinase and HDAC inhibitor. ACS medicinal chemistry letters 36 24015327
2006 Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation. Breast cancer research and treatment 36 16267617
2018 c-Src activity is differentially required by cancer cell motility modes. Oncogene 35 29379163
2015 Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis. Frontiers in physiology 34 26696895
2009 A novel role for c-Src and STAT3 in apoptotic cell-mediated MerTK-dependent immunoregulation of dendritic cells. Blood 34 19667404
2000 Stimulation of c-Src by prolactin is independent of Jak2. The Biochemical journal 34 10600634
2002 Involvement of PI3-kinase and its association with c-Src in PTH-stimulated rat enterocytes. Journal of cellular biochemistry 32 12210743
1979 The src gene product of transformed and morphologically reverted ASV-infected mammalian cells. Nature 31 225672
2023 Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression. The Journal of clinical investigation 29 36795481
2020 c-Src promotes the growth and tumorigenesis of hepatocellular carcinoma via the Hippo signaling pathway. Life sciences 28 33186566
2001 Melanoma cells stimulate osteoclastogenesis, c-Src expression and osteoblast cytokines. European journal of cancer (Oxford, England : 1990) 28 11290439
2019 RNF43 ubiquitinates and degrades phosphorylated E-cadherin by c-Src to facilitate epithelial-mesenchymal transition in lung adenocarcinoma. BMC cancer 27 31286874
2021 c-Src facilitates tumorigenesis by phosphorylating and activating G6PD. Oncogene 26 33686238
2021 Paradoxical activation of c-Src as a drug-resistant mechanism. Cell reports 26 33761359
2017 Alamandine reduces leptin expression through the c-Src/p38 MAP kinase pathway in adipose tissue. PloS one 26 28591164
2016 c-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II-Induced Hypertension. Hypertension (Dallas, Tex. : 1979) 26 27620391
2001 Involvement of c-Src in carcinoma cell motility and metastasis. Japanese journal of cancer research : Gann 26 11572761
2019 EGFR-c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells. Cells 25 31430896
2020 EGFR/FAK and c-Src signalling pathways mediate the internalisation of Staphylococcus aureus by osteoblasts. Cellular microbiology 24 32584493
2019 Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis. Nature communications 23 31420536
2016 Memo interacts with c-Src to control Estrogen Receptor alpha sub-cellular localization. Oncotarget 23 27472465
2016 c- Src and its role in cystic fibrosis. European journal of cell biology 23 27530912
2020 Glycation of fibronectin inhibits VEGF-induced angiogenesis by uncoupling VEGF receptor-2-c-Src crosstalk. Journal of cellular and molecular medicine 22 32613750
2019 RACK1 interaction with c-Src is essential for osteoclast function. Experimental & molecular medicine 22 31358728
1997 Role of c-Src in cellular events associated with colony-stimulating factor-1-induced spreading in osteoclasts. Molecular reproduction and development 22 8981371
2023 CircKIF4A combines EIF4A3 to stabilize SDC1 expression to activate c-src/FAK and promotes TNBC progression. Cellular signalling 21 37121557
2020 c-Src kinase impairs the expression of mitochondrial OXPHOS complexes in liver cancer. Cellular signalling 21 32335258
2019 Autophosphorylation activates c-Src kinase through global structural rearrangements. The Journal of biological chemistry 21 31331936
2009 The PDZ protein MPP2 interacts with c-Src in epithelial cells. Experimental cell research 21 19665017

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