Disease relevance of Src

• Herbal formulation, Yukmi-jihang-tang-Jahage, regulates bone resorption by inhibition of phosphorylation mediated by tyrosine kinase Src and cyclooxygenase expression [1].
• CONCLUSIONS: In contrast to divalent cations, extracellular pressure may increase integrin affinity and promote colon cancer adhesion via actin dependent inside-out FAK and Src signals [2].
• Previously, we established a role for the nonreceptor tyrosine kinase Src in signaling cardiac myocyte hypertrophy [3].
• Furthermore, Src co-precipitated with the P2Y(2) receptor in 1321N1 astrocytoma cells stimulated with the P2Y(2) receptor agonist UTP [4].
• SynGAP bound to the SH2 domains of Src and Fyn in a tyrosine phosphorylation-dependent fashion, and this interaction increased after ischemia [5].

Psychiatry related information on Src

• Lateral hypothalamic signaling mechanisms underlying feeding stimulation: differential contributions of Src family tyrosine kinases to feeding triggered either by NMDA injection or by food deprivation [6].

High impact information on Src

• The G betagamma-responsive ERK activation induced by H2O2 is independent of ligands binding to Gi-coupled receptors, but requires phosphatidylinositol-3-kinase and Src activation [7].
• Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases [8].
• NMDA-receptor-mediated whole-cell currents and NMDA-receptor single-channel activity were increased by raising [Na+]i and channel activity decreased upon lowering [Na+]i; therefore, the activity of NMDA channels tracks changes in [Na+]i. We found that the sensitivity of the channel to Na+ was set by a Src kinase that is associated with the channel [9].
• It achieves this, at least in part, by binding and activating one of the non-receptor tyrosine kinases, pp60c-src, pp62c-yes or pp59c-fyn (reviewed in refs 2 and 3) [10].
• Thus, Src activation is necessary and sufficient for inducing LTP and may function by up-regulating NMDA receptors [11].

Chemical compound and disease context of Src

• In the cells treated with CGS21680, PI3K activation was prevented either by inhibiting adenylate cyclase and PKA with, respectively, 2,5-dideoxyadenosine and H89 or by blocking Galphai-protein and Src tyrosine kinase with, respectively, pertussis toxin and PP2 [12].
• The large (130kDa), multi-domain Cas molecule contains an SH3 domain, a Src-binding domain, a serine-rich protein interaction region, and a C-terminal region that participates in protein interactions implicated in antiestrogen resistance in breast cancer [13].
• Langendorff rat heart preparations were exposed to 50 microM ouabain to produce positive inotropy without toxicity, and assayed for Src kinase, protein kinase C, and extracellular signal-regulated kinases 1 and 2 (ERK(1/2)) [14].
• Upregulation of c-Src signaling may be important in the profibrotic and proinflammatory actions of aldosterone in this genetic model of hypertension [15].
• Here, we describe a novel class of Src inhibitors, substituted 5,7-diphenyl-pyrrolo[2,3-d]pyrimidines, and characterize one of them, CGP77675, in vitro and in models of bone resorption in vivo [16].

Biological context of Src

• RESULTS: TUDC induced a rapid activation of focal adhesion kinase (FAK) and Src, as shown by an increase in Y418 phosphorylation and a decrease in Y529 phosphorylation of Src [17].
• Src, PI3K, and PKC-iota were likewise required for NGF-induced NF-kappaB activation and cell survival, whereas Ras was not required for either survival or NF-kappaB activation but was required for differentiation [18].
• Experiments with the Src inhibitor, PP2, and the antioxidant N-acetyl-L-cysteine revealed critical roles for Src and reactive oxygen species as upstream mediators of EGFR transactivation in response to PPAR ligands [19].
• Role of Src-induced dynamin-2 phosphorylation in caveolae-mediated endocytosis in endothelial cells [20].
• In contrast, p38 activation by PPARalpha and gamma ligands occurred independently of Src, oxidative stress, the EGFR, and Ras [19].

Anatomical context of Src

• Although the requirement for c-Src in extracellular matrix (ECM)-mediated fibroblast motility has been well established, the roles of hemopoietic Src family protein tyrosine kinases in leukocyte migration have not been fully elucidated [21].
• ConA inhibited AT(1) receptor internalization without affecting ligand binding to the receptor, Ang II-induced generation of second messengers, and activation of tyrosine kinases Src and Pyk2 in vascular smooth muscle cells (VSMC) [22].
• We addressed the role of Src phosphorylation of the GTPase dynamin-2 in the mechanism of caveolae release and albumin transport [20].
• Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade [23].
• Here we demonstrated that Ang II rapidly and significantly stimulated tyrosine phosphorylation of Src and Cas and their association in rat aortic smooth muscle cells (RASMC) [24].

Associations of Src with chemical compounds

• Integrin-dependent Src activation was also identified as an upstream event in hypo-osmotic signaling toward MAPKs and choleresis [17].
• CONCLUSIONS: TUDC-induced stimulation of canalicular taurocholate excretion involves integrin sensing, FAK, and Src activation as upstream events for dual MAPK activation [17].
• Proliferation was also evaluated in normal purified cholangiocytes treated with 17 beta estradiol in the presence or absence of tamoxifen, Ici 182,780, ERK, or Src inhibitors [25].
• Therefore, alpha(5)beta(1) integrin appears to regulate a tyrosine phosphorylation cascade involving Src and various focal adhesion proteins that control the function of the L-type calcium channel [26].
• GIT1 mediates Src-dependent activation of phospholipase Cgamma by angiotensin II and epidermal growth factor [27].
• The kinase domain of ILK, including proline-rich regions, appeared to interact physically with the Src homology 3 domain of c-Src [28].
• GABA(A) receptor agonist muscimol could attenuate Src activation and interactions among NR2A, PSD-95 and Src, resulting the suppression of NMDA receptor tyrosine phosphorylation [29].
• The present data suggest a possible control point in the regulation of respiration by tyrosine phosphorylation of the complexes mediated by Src auto-activation [30].

Physical interactions of Src

• DPP IV coimmunoprecipitated with the cellular tyrosine kinase Src (c-Src) with maximal association also observed after 2 min following insulin injection [31].
• Indeed, the formation of p-FAK/c-Src protein complex, but not their association with beta1-integrin, was stimulated during T suppression-induced germ cell loss [32].
• Infection of cardiomyocytes with an adenovirus expressing a mutant Pyk2 which lacked its kinase domain or its ability to bind to c-Src, eliminated ET-1- and PE-induced hypertrophic responses [33].
• The purified caveolin-1 binds c-Src, suppressing its autophosphorylation [34].
• Coimmunoprecipitation studies revealed decreased binding of ZO-1 and increased binding of c-Src to Cx43 at low pHi [35].

Enzymatic interactions of Src

• In the present investigation, we report that tamalin possesses a typical immunoreceptor tyrosine-based activation motif (ITAM), which enables Syk kinase to be recruited and phosphorylated by the Src family kinases [36].
• Tyr(124) is phosphorylated by Src in vitro; in whole cells, Y124F Kv2.1 is significantly less phosphorylated by Src and loses most of its ability to bind the D245A substrate-trapping mutant of cyt-PTPepsilon [37].
• Also, addition of c-Src and [(32)P]ATP phosphorylated the synthesized peptide corresponding to amino acid sequence 333-362 of the COOH terminus of ROMK1 [38].
• Upon E2 treatment, Src kinase is tyrosine phosphorylated, which, in turn, stimulates Src kinase to phosphorylate caveolin-1 [39].
• Src family kinases have been shown to phosphorylate PLC-gamma 1 and to be activated by G protein-coupled receptors [40].

Regulatory relationships of Src

• These data indicate that Ang II induces Ca2+-dependent transactivation of the EGF receptor which serves as a scaffold for pre-activated c-Src and for downstream adaptors, leading to MAPK activation in VSMC [41].
• At the mechanistic level, Ca(2+) chelator (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)), phosphatidylinositol-phospholipase C inhibitor (U73122), or Src inhibitor (PP2) attenuated the PGE(2)-induced Fn expression [42].
• The involvement of Src-tyrosine kinase activity was demonstrated by detection of increased c-Src phosphorylation in response to E(2) and by blockade of E(2)-induced ERK1/2 activation by inhibition of Src-family tyrosine kinase activity [43].
• Together our results suggest that PSD-95 may be important for localizing and/or regulating multiple Src protein tyrosine kinases at the NMDA receptor multiprotein complex [44].
• The c-Src inhibitor PP2 inhibited DPP IV phosphorylation [31].
• Using a thermoactivatable mutant of v-Src, we show that at the permissive temperature, annexin 2 becomes phosphorylated and colocalizes with activated v-Src and focal adhesion kinase both at the plasma membrane and in a Rab11-positive compartment of the endosomal pathway [45].

Other interactions of Src

• Both EGFR and non-receptor tyrosine kinase p60Src, whose kinase activities were required in the sensitization, were found to be enriched in cholesterol-rich lipid rafts [46].
• Sensitization of epidermal growth factor-induced signaling by bradykinin is mediated by c-Src. Implications for a role of lipid microdomains [46].
• Prostaglandin E2 stimulates fibronectin expression through EP1 receptor, phospholipase C, protein kinase Calpha, and c-Src pathway in primary cultured rat osteoblasts [42].
• Thus, Src-mediated phosphorylation of dynamin-2 is an essential requirement for scission of caveolae and the resultant transendothelial transport of albumin [20].
• The mechanism by which ERKs-1 and -2 are activated by estrogen appears to be independent of c-Src since the effects of estrogen on PRL gene expression are not affected by herbimycin A or PP1 administration. c-Raf-1 may be involved in the effects of E2 because estrogen causes the rapid and transient tyrosine phosphorylation of c-Raf-1 [47].

Analytical, diagnostic and therapeutic context of Src

• Activated MAPK, Pyk2, and c-Src amounts were measured by Western blot analysis [48].
• By immunoelectron microscopy, we demonstrate that, unlike Src, the Src-related kinases are associated with electron-dense cytoplasmic domains and plasma membrane domains that correspond in size and frequency to endocytotic vesicles and coated pits [49].
• Co-immunoprecipitation identified an association between the channel protein and Src [50].
• Immunoblot using clone 28, a monoclonal antibody specific for the active form of Src kinases, demonstrated increased active Src expression in the injured rat kidney 6 hours after reperfusion with peak activation at 12 hours [51].
• Immunohistochemistry using clone 28 demonstrated that active Src was preferentially expressed in the S3 segment of the proximal tubule in reperfused kidney, where it is not normally expressed [51].

References