Disease relevance of CSK

• Taken together, these findings strongly suggest that CD44 interaction with c-Src kinase plays a pivotal role in initiating cortactin-regulated cytoskeleton function and HA-dependent tumor cell migration, which may be required for human ovarian cancer progression [1].
• Tyrosine nitration of c-SRC tyrosine kinase in human pancreatic ductal adenocarcinoma [2].
• Because ERalpha and c-Src have been shown to interact in a number of different systems, we wanted to evaluate the role of c-Src kinase in estrogen-stimulated growth and survival of ERalpha-positive breast cancer cells [3].
• The expression of CSK obtained from human colorectal cancer cell lines was greater than that from human colorectal normal cell lines in most cases [4].
• We confirmed this result by showing that expression of two inhibitors of Src family function, dominant-negative-Src and CSK, also suppressed glioma cell invasion [5].

High impact information on CSK

• This activity depends on the membrane recruitment and activation of c-Src kinase, thus uncovering a new role in endosome function [6].
• Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis [7].
• They also suggest a central role of c-src kinase in the cross-talk between tyrosine kinase receptor and GPCR [8].
• Coupling of M2 muscarinic receptor to L-type Ca channel via c-src kinase in rabbit colonic circular smooth muscle [8].
• Here we show that c-Src tyrosine kinase is activated by dsRNA in human monocyte-derived dendritic cells, and is recruited to TLR3 in a dsRNA-dependent manner [9].

Chemical compound and disease context of CSK

• In this study we report that OPN induces alpha(v)beta(3) integrin-mediated c-Src kinase activity in both highly invasive (MDA-MB-231) and low invasive (MCF-7) breast cancer cells [10].

Biological context of CSK

• Finally, overexpression of a dominant-negative mutant of c-Src kinase (K295R) in SK-OV-3.ipl cells impairs the tumor cell-specific phenotype [1].
• CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration [1].
• This gene and CSK shared some unique structural properties such as the absence of a myristylation signal and phosphorylation sites of tyrosine residues corresponding to tyrosines 416 and 527 of chicken p60c-src [11].
• These findings establish close relationship between the HYL and CSK genes and also suggest that HYL may play an important role in signal transduction through SRC-family kinases in the central nervous system [12].
• By regulating the activity of these kinases, CSK may play an important role in cell growth and development [13].

Anatomical context of CSK

• In this study we have demonstrated that both CD44 (the hyaluronan (HA) receptor) and c-Src kinase are expressed in human ovarian tumor cells (SK-OV-3.ipl cell line), and that these two proteins are physically associated as a complex in vivo [1].
• We also observed that fibroblasts stimulated with IGF-I or insulin showed a rapid and transient decrease in c-Src tyrosine kinase activity [14].
• Northern blot analysis revealed a 2.2 kb transcript in various myeloid cell lines but not in adult tissues except for the brain and the lung, whereas CSK mRNA was ubiquitously expressed [11].
• FAK associates with CSK 48 h after infection and recruits it to focal contacts [15].
• De novo expression of pp125FAK in human macrophages regulates CSK distribution and MAP kinase activation but does not affect focal contact structure [15].

Associations of CSK with chemical compounds

• CSK phosphorylates other members of the src-family of tyrosine kinases at their regulatory carboxy-terminus [13].
• In a mitogenesis assay measuring thymidine incorporation stimulated by specific mitogens, the c-Src tyrosine kinase inhibitors reduced incorporated thymidine in a manner consistent with previously reported roles of c-Src in mitogenic signaling [16].
• We have previously reported the activation of c-Src tyrosine kinase during ovarian steroid-induced decidualization of cultured human endometrial stromal cells [17].
• One of these, an approximately 62-kDa protein, also associated with CSK in NIH 3T3 cells treated with vanadate prior to lysis and in NIH 3T3 cells expressing an activated c-Src mutant [18].
• The interaction between CSK and GAP-A.p62 could be reconstituted in vitro with glutathione S-transferase fusion proteins containing full-length CSK or the CSK SH2 domain [18].

Physical interactions of CSK

• We show the high PAG-binding ability with CSK in vitro as well as the human PAG structure characterized by 11 alpha-helix structures including a 3 kDa transmembrane domain [19].
• We show that in the early phases of cell adhesion integrins associate with EGF receptors on the cell membrane in a macromolecular complex including the adaptor protein p130Cas and the c-Src kinase, the latter being required for adhesion-dependent assembly of the macromolecular complex [20].
• 3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases [21].

Enzymatic interactions of CSK

• We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR [14].
• 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 [22].
• In vivo S2V was tyrosine-phosphorylated when co-expressed with exogenous c-Src kinase [23].
• Changing all of these sites to phenylalanine resulted in a villin mutant that neither was phosphorylated in TKX1 cells nor was a substrate for c-src kinase in an in vitro kinase assay [24].

Regulatory relationships of CSK

• VEGF stimulation specifically activated c-Src kinase activity but not that of other related Src kinases such as Lyn, Fyn, or Hck in KS cells [25].
• Signal transduction through extracellular signal-regulated kinase-like pp57 blocked in differentiated colon carcinoma cells having low levels of c-src kinase [26].
• The stimulation of neutrophil-like differentiated HL60 cells with TNF-alpha induced activation of NFkappaB and c-Src kinase, and the activation was attenuated by treatment with the anti-oxidants [27].
• In addition, it has been shown previously that occupancy of the c-Src SH2 domain with a phosphopeptide stimulates c-Src kinase catalytic activity [28].
• The activity of the c-Src kinase localized at the focal adhesion plaques appears to be regulated by cell adhesion to the extracellular matrix [29].

Other interactions of CSK

• We observed that the IGF-IR and IR associated with the C-terminal Src kinase (CSK) following ligand stimulation [14].
• Even though CD85j was detected in both anti-SHP1 and CSK immunoprecipitates, these two molecules did not co-precipitate together with CD85j [30].
• Characterization of two activated mutants of human pp60c-src that escape c-Src kinase regulation by distinct mechanisms [22].
• Unlike CSK, the SH3 domain of HYL was unique since the ALYDY motif was absent [11].
• Sam68 is a 68 kDa protein that associates with and is phosphorylated by the c-Src kinase at mitosis [31].

Analytical, diagnostic and therapeutic context of CSK

• We have here mapped the CSK gene to 15q23----q25 by in situ hybridization [32].
• Immunoprecipitation coupled with Western analysis identified c-Src tyrosine kinase as a target of both tyrosine nitration and tyrosine phosphorylation [2].
• To identify phosphotyrosine (P.Tyr)-containing proteins that may mediate translocation of CSK due to c-Src activation, we have examined the whole spectrum of P.Tyr-containing proteins that associate with CSK in v-Src NIH 3T3 cells by anti-P.Tyr immunoblotting [18].
• CSK and TPK-IIB once resolved from each other by heparin-Sepharose affinity chromatography, display opposite specificities toward synthetic peptides reproducing the sequences around the main phosphoacceptor residues of pp60c-src, namely Tyr-416 and Tyr-527 [33].
• Biochemical and site-directed mutagenesis analyses revealed that a carboxy-terminal peptide of p54rak was phosphorylated by a cytoplasmic tyrosine kinase (CSK) and that, as in the Src family, it is the COOH-terminal tyrosine that is phosphorylated by CSK [34].

References