Disease relevance of Src

• Taken together, these findings suggest that Src-dependent tyrosine phosphorylation of PYK2 is involved in the adhesion-induced formation of the sealing zone, required for osteoclastic bone resorption [1].
• Src-deficient mice exhibit functional abnormalities in only one myeloid cell type, the osteoclast, resulting in impaired bone remodeling and osteopetrosis, while hck-/- or fgr-/- mice have few and subtle myeloid cell deficiencies [2].
• Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells [3].
• Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras [4].
• We detected an increase in Src proto-oncogene activity within 15-30 min of cellular exposure to hypoxia [5].

Psychiatry related information on Src

• Infection of newborn or 2-week-old Src-negative mice with a retrovirus encoding middle T led to the induction of visceral hemangiomas that were indistinguishable from tumors in wild-type mice with respect to their morphology, frequency or latency period [6].

High impact information on Src

• For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes [7].
• The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl [8].
• Src kinases in Ph+ lymphoblastic leukemia [9].
• Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases [10].
• These data demonstrate that the Src family tyrosine kinases are direct effectors of G proteins [10].

Chemical compound and disease context of Src

• Polycythemia and reticulocytosis responded to treatment with imatinib or a JAK2 inhibitor, but were unresponsive to the Src inhibitor dasatinib [11].
• SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice [12].
• Involvement of G(i) proteins and Src tyrosine kinase in TNFalpha production induced by lipopolysaccharide, group B Streptococci and Staphylococcus aureus [13].
• AG 879, in combination of PP1 (an inhibitor specific for Src kinase family), suppresses almost completely the growth of RAS-induced sarcomas in nude mice [14].
• The objective of this study was to analyse the role of c-Src in the (alpha)(v)(beta)(3) integrin-dependent recruitment of signalling and cytoskeletal molecules in osteoclasts during bone resorption [15].

Biological context of Src

• A target for Src in mitosis [16].
• The activity of the c-Src protein is increased during cell-cycle stage G1 in fibroblasts stimulated with certain growth factors, and at the G2/M transition, but little is known about Src substrates in these circumstances [16].
• We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some vesicular structures [17].
• Our data suggest that Src kinases control the transcriptional activation of Myc [18].
• Thus, Src family kinases and proteins associating with their SH2 domains are required for entry into mitosis [19].

Anatomical context of Src

• Lck is the major Src family member required for thymopoiesis, since there is a severe deficit of CD4+CD8+ thymocytes and mature T cells in its absence [20].
• Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development [21].
• Translocation of Src kinase to the cell periphery is mediated by the actin cytoskeleton under the control of the Rho family of small G proteins [22].
• Thus, we conclude that translocation of Src from its site of synthesis to its site of action at the cell membrane requires an intact cytoskeletal network and that the small G proteins of the Rho family may specify the peripheral localization in focal adhesions or along the membrane, mediated by their effects on the cytoskeleton [22].
• Stable transfection of selected SH3 domain mutants into NIH-3T3 cells showed that despite elevated levels of phosphotyrosine, the cells were morphologically normal, indicating that the SH3 domain was required for efficient transformation of NIH-3T3 cells by Src [23].

Associations of Src with chemical compounds

• We compared the phosphotyrosine content of growing and mitotically arrested Src-transformed cells [16].
• Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division [19].
• We find here that Src associates constitutively with integrin alphaIIbbeta3 in platelets [24].
• Proline-rich sequences that bind to Src homology 3 domains with individual specificities [25].
• One clone that binds to both Src and Abl SH3 domains through a common site exhibits reversed binding orientation, in that an arginine indispensable for binding to all tested SH3 domains occurs at the C terminus [25].

Physical interactions of Src

• The c-cbl protooncogene product (c-Cbl) is a 120-kDa protein that has been shown to bind to the Src homology 3 domains of various proteins, suggesting its involvement in signal transduction pathways [26].
• Furthermore, we show that this interaction is direct and that Grb2 binds to phospho-AbetaPP via its Src homology 2 region [27].
• Eliminating the Src-binding site on Pyk2 (Pyk2(Y402F)) markedly inhibited bone resorption by osteoclast-like cells, whereas kinase-dead Pyk2 had little effect [28].
• Autophosphorylation of PDGF receptors upon ligand stimulation provides binding sites for Src homology 2 domains of intracellular signaling molecules, which thereby become activated [29].
• Furthermore, this tyrosine phosphorylated protein was not detected in c-Src complexes derived from fibroblasts transformed by either Neu or PyV middle T [30].

Enzymatic interactions of Src

• This heteromolecular complex is coordinated by proline-rich and Src family-dependent phosphorylated regions of M2 [31].
• In contrast, expression of a cortactin mutant lacking tyrosine residues phosphorylated by Src did not restore podosome formation [32].
• In summary, we show that CN-induced chemical anoxia activates c-Src and induces its translocation to cell-cell junctions where it binds to and phosphorylates beta-catenin and p120 [33].
• Sam68 is the major tyrosine-phosphorylated and Src-associated protein in mitotic cells [34].
• Src phosphorylates the insulin-like growth factor type I receptor on the autophosphorylation sites. Requirement for transformation by src [35].

Co-localisations of Src

• Upon activation of PKC, RACK1 co-localizes with the Src tyrosine kinase at the plasma membrane and functions as a substrate, binding partner and inhibitor of Src (as measured in vitro), and a growth inhibitor in NIH 3T3 cells [36].

Regulatory relationships of Src

• Tr-kit-induced resumption of the cell cycle in mouse eggs requires activation of a Src-like kinase [37].
• We also measured the levels of Src kinase activity in cell lines expressing isoforms of the Ret receptor activated by different mutations [38].
• We next tested reconstruction of the signaling in the membrane-anchored, gain-of-function Csk-expressing cells by introducing Src family kinases the C-terminal negative regulatory sequence of which was replaced with a c-myc epitope [39].
• Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2 [40].
• In addition, we demonstrated that the Src-induced response was down-regulated by Gab2-associated SHP2 [40].

Other interactions of Src

• The engagement of these receptors leads to the activation of Lck and Fyn, which are protein tyrosine kinases (PTKs) of the Src family [41].
• c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption [17].
• The p68 was physically associated with activated c-Src, and it bound to the SH3 domain of c-Src in vitro [16].
• Fyn and Yes, the other members of the Src family present in fibroblasts, were also found to be activated at mitosis [19].
• Two families of protein tyrosine kinases (PTKs), the Src and Syk/ZAP-70 families, are required for T cell development [20].

Analytical, diagnostic and therapeutic context of Src

• To assess the relevance of Src inhibition to angiogenesis, in vivo gelfoam assays were done [42].
• Based on coprecipitation analysis and two-color immunofluorescence, this heterologous Src family kinase was observed to physically associate with the B cell Ag receptor [43].
• We also compared the tyrosine-phosphorylation status of