Disease relevance of SRC

• Expression and activity of SRC regulate interleukin-8 expression in pancreatic adenocarcinoma cells: implications for angiogenesis [1].
• SRC family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells [2].
• Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model [3].
• Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells [4].
• The SRC-induced mesenchymal state in late-stage colon cancer cells [5].

Psychiatry related information on SRC

• After spatial maze learning, up-regulation of c-src mRNA was observed in the CA3 region of the hippocampus, which was accompanied by increases in pp60c-src protein in hippocampal synaptosomal preparations [6].

High impact information on SRC

• Autoinhibited c-Abl forms an assembly that is strikingly similar to that of inactive Src kinases but with specific differences that explain the differential ability of the drug STI-571/Gleevec/imatinib (STI-571) to inhibit the catalytic activity of Abl, but not that of c-Src [7].
• EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake [8].
• We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis [9].
• Activating SRC mutation in a subset of advanced human colon cancers [9].
• The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c-Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human cancers. c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver [9].

Chemical compound and disease context of SRC

• Hypoxia increases the kinase activity of pp60c-src and its phosphorylation on tyrosine 416 but does not activate Fyn or Yes [10].
• These results show that the prostaglandin E/beta-arrestin 1/c-Src signaling complex is a crucial step in PGE(2)-mediated transactivation of the EGFR and may play a pivotal role in tumor metastasis [11].
• Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b [12].
• Underexpressed Coactivators PGC1{alpha} AND SRC1 Impair Hepatocyte Nuclear Factor 4{alpha} Function and Promote Dedifferentiation in Human Hepatoma Cells [13].
• The effects of PMA on MAPK phosphorylation and glioblastoma cell proliferation were reduced by BIM, rottlerin, the MEK inhibitor U0126, and PKCdelta and c-Src siRNAs [14].

Biological context of SRC

• These observations demonstrate a role for SRC kinase in modification and recruitment of clathrin during ligand-induced EGFR endocytosis and thereby define a novel effector mechanism for regulation of endocytosis by receptor signaling [8].
• These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck [15].
• The TALL-103 cell lines provide a unique system to study the interaction between lymphokines and SRC-family PTKs in signal transduction pathways leading to hematopoietic cell differentiation [16].
• As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution [4].
• These data suggest that the transactivation capacity of various ER isoforms is both SRC species and cell type dependent [17].

Anatomical context of SRC

• Activation of SRC tyrosine kinases in response to ICAM-1 ligation in pulmonary microvascular endothelial cells [18].
• PP1, an inhibitor of SRC family kinases, blunted both the A(2A)-receptor- and the forskolin-induced MAP kinase stimulation (IC(50) = 50 nm); this was also seen in PC12 cells, which express the A(2A)-receptor endogenously, and in NIH3T3 fibroblasts, in which cAMP causes MAP kinase stimulation [19].
• The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells [4].
• SRC kinase and mitogen-activated protein kinases in the progression from normal to malignant endometrium [20].
• To address this problem, we transfected MCF-7 cells to express the noncatalytic carboxylterminal domain of focal adhesion kinase (FAK), FAK(Y397F), kinase-defective c-Src, or Shc FFF, all of which express dominant-negative activity [21].

Associations of SRC with chemical compounds

• Taken together, these data support a role for the SRC family of transcriptional coactivators in TCDD-dependent gene regulation [22].
• Cross-linking ICAM-1 on tumor necrosis factor-alpha-pretreated ECs induced an increase in the activity of SRC tyrosine kinases [18].
• Phenylarsine oxide, a tyrosine phosphatase inhibitor, reduced the base-line activity of SRC as well as the increase in SRC activity induced by ICAM-1 cross-linking [18].
• Furthermore, phosphorylation of p52Shc by c-Src is essential for its recruitment to EphB1 signaling complexes through its phosphotyrosine binding domain [23].
• Here, we examined the effects that different ERalpha ligands have on coactivator protein steady-state levels and demonstrate that the selective ER modulators (SERMs) 4-hydroxytamoxifen (4HT) and raloxifene are able to elevate SRC-1 and SRC-3 protein levels [24].
• During decidualization, STAT5 was phosphorylated on tyrosine 694, a well-known SRC phosphorylation site [25].

Physical interactions of SRC

• Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases [26].
• The results demonstrate that the c-Src SH2 domain binds directly to pYEKV and inhibits the interaction between MUC1 and GSK3 beta [27].
• Moreover, PYK2 formed a complex coprecipitable with catalytically active c-Src after Ang II stimulation [28].
• Bone morphogenetic protein receptor type II C-terminus interacts with c-Src: implication for a role in pulmonary arterial hypertension [29].
• In vitro studies using coimmunoprecipitation experiments and a yeast three-hybrid assay reveal that c-Src stabilizes the agonist-independent association between beta-arrestin2 and the beta-subunit of AP-2 independently of the kinase activity of c-Src [30].

Enzymatic interactions of SRC

• Under these in vitro conditions, E381G c-Src was found to be phosphorylated by CSK to wild-type levels, while E527K c-Src was not detectably phosphorylated [31].
• In coimmunoprecipitation experiments, IKKalpha/beta was found to be associated with c-Src and to be phosphorylated on its tyrosine residues after TNF-alpha or TPA treatment [32].
• The C-terminal autophosphorylation domain of EGFR was extensively phosphorylated by c-src and EGFR kinase activities in vitro as determined by electrospay ionization mass spectrometry [33].
• Our results support a model in which activated c-Src phosphorylates the COOH-terminal tail of Cx43 on residue Tyr(265), resulting in a stable interaction between both proteins leading to inhibition of gap junctional communication [34].
• We demonstrate that c-Src can directly phosphorylate GRK2 on tyrosine residues, as shown by in vitro experiments with purified proteins [35].

Co-localisations of SRC

• Experiments in c-Src depleted cells reveal that AT1R remained mostly colocalized with AP-2 at the plasma membrane after Ang II stimulation, consistent with the observed delay in receptor internalization [30].

Regulatory relationships of SRC

• Pyk2 amplifies epidermal growth factor and c-Src-induced Stat3 activation [36].
• c-Src regulates clathrin adapter protein 2 interaction with beta-arrestin and the angiotensin II type 1 receptor during clathrin- mediated internalization [30].
• Results from Western blots, c-Src is involved in LPC-induced Flk-1/KDR transactivation because herbimycin A and PP2 inhibited this transactivation [37].
• Here we sought to determine whether c-Src regulates the recruitment of AP-2 to beta-arrestin and the angiotensin II (Ang II) type 1 receptor (AT1R) during internalization [30].
• Stimulation of beta2 adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor [38].
• CSK blocked the RAR-RA-dependent activation of SRC and neurite outgrowth in LA-N-5 cells [39].

Other interactions of SRC

• Our results provide an insight into hypoxia-triggered intracellular signalling, define VEGF as a new downstream target for c-SRC, and suggest a role for c-SRc in promoting angiogenesis [10].
• Expression of dominant-negative c-Src significantly reduced EphB1-dependent ERK1/2 activation and chemotaxis [23].
• In particular, we found that EGF receptors, but not beta(2)-adrenergic receptors, activated c-Src by a Ral-GTPase-dependent mechanism [40].
• Furthermore, we identify two tyrosine residues that are subject to phosphorylation in response to muscarinic signaling and show that this phosphorylation induces two cytosolic proteins, c-Src and Grb2, to bind to PYK2 [41].
• Dok-R mediates attenuation of epidermal growth factor-dependent mitogen-activated protein kinase and Akt activation through processive recruitment of c-Src and Csk [42].

Analytical, diagnostic and therapeutic context of SRC

• Site-directed mutagenesis experiments demonstrate that tyrosines 600 and 778 of EphB1 are required for its interaction with c-Src and p52Shc [23].
• In addition, gene copy number of SRC1 was analyzed by fluorescence in situ hybridization [43].
• Paradoxically, the SRC1 gene was found to be amplified and highly expressed in a LuCaP 70 prostate cancer xenograft [43].
• Immunohistochemistry demonstrated that SRC-1 and N-CoR stain positive in the glandular epithelium and stroma in menstrual phase endometrium [44].
• By using a real-time RT-PCR assay, we showed that SRC-1, N-CoR and SMRT mRNA are expressed in human endometrium during all phases of the menstrual cycle, as well as in inactive endometrium [44].

References