How is c src activation

B , , 15 , — Article Views Altmetric -. Citations Supporting Information. Cited By. This article is cited by 24 publications. Journal of Medicinal Chemistry , 64 20 , The Journal of Physical Chemistry A , 34 , Journal of Chemical Theory and Computation , 16 3 , Journal of Chemical Theory and Computation , 14 5 , Accounts of Chemical Research , 50 5 , Tyrosine kinases: complex molecular systems challenging computational methodologies.

Journal of Biomolecular Structure and Dynamics , 38 , The Journal of Chemical Physics , 17 , Loratadine, an antihistamine drug, exhibits anti-inflammatory activity through suppression of the NF-kB pathway. Biochemical Pharmacology , , Glycine substitution in SH3-SH2 connector of Hck tyrosine kinase causes population shift from assembled to disassembled state. Leucine rich repeats and calponin homology domain containing 1 inhibits NK cell cytotoxicity through attenuating Src signaling.

Immunobiology , 3 , Dynamic regulatory features of the protein tyrosine kinases. Biochemical Society Transactions , 47 4 , Mader , Andreas Seidl , Ville R. Kaila , Johannes Buchner. Src kinase activity, from 4—fold higher than normal tissues, has been found in human mammary carcinomas Egan et al. Similarly, cell lines derived from these tumors display up to a fold elevation in Src activity.

Recent data has suggested some of this activity may be attributable to the action of phosphatases resulting in dephosphorylation of Tyr Egan et al. Rosen et al. On the other hand, Verbeek et al. Ottenhoff-Kalff et al. Activated Src in mammary tumors has been well studied in transgenic mice. Mice expressing viral polyoma middle T antigen under the control of the MMTV promoter produce highly metastatic mammary tumors with elevated c-Src kinase activity Guy et al.

Muthuswamy et al. These are two examples of activated Src, one an example of a viral protein binding and activating Src, causing tumors, and the other an example of a receptor tyrosine kinase causing Src activation and subsequent mammary tumors. Nude mouse experiments Biscardi et al. This supports the hypothesis that Src activation can be mediated through HER1 interactions. The c- src proto-oncogene has frequently been implicated in the initiation and progression of human colon cancer, and in resultant metastases Bolen et al.

Src activity is increased 5—8-fold in the majority of colon tumors. This elevation of Src activity, and of the related Yes activity, is an early event, occurring even in premalignant tissues Cartwright et al. Activity is apparently high in malignant polyps and in benign polyps that contain villous change or severe dysplasia, which are at greatest risk for developing cancer.

Src activity was also found to be elevated in mildly dysplastic epithelia 6—fold when compared directly with adjacent non-dysplastic epithelia in ulcerative colitis, increasing further in severely dysplastic tissue which is at greatest risk of developing cancer Cartwright et al. A role for Src in tumor progression is poignantly illustrated by observations that Src activity increases with the progression of colon tumors, being higher in primary tumors than in polyps and higher yet in metastatic liver lesions Talamonti et al.

The trend is reflected in six paired samples of synchronous primary and metastatic lesions from the same patient. While Src protein levels vary widely between patients, the activity level increases in liver metastases over that of synchronous primary tumors—several fold greater than the increases in Src protein levels.

Further differences exist in the levels of activated Src seen in colorectal metastases to extrahepatic sites Termuhlen et al. In addition, colorectal metastases to abdomen, pelvis, and thorax showed a significant increase in activity over hepatic metastases. These data raise the question as to whether the site of metastasis influences the specific activity of Src or whether the specific activity of Src influences the site of the metastatic lesion.

The influence of Src in colon cancer has also been explored by examination of Src levels in colon tumors of various differentiation states. The reported results are interesting but not always intuitive. Weber et al. Park et al. These results, on the surface, are difficult to interpret knowing that poorly differentiated tumors are biologically more aggressive than well-differentiated tumors. The majority of colorectal liver metastases, however, are in fact well-to-moderately differentiated and this prevalence may explain the observed results.

The role of Src in colon cancer has been recently examined using the nude mouse model injected with various colon cancer cell lines Irby et al. Staley et al. When injected into nude mice, these cells formed slowly growing tumors with a proliferation rate retarded further than the reduced proliferation rate of parental cells grown in culture. In contrast, cells stably transfected with a sense vector showed no difference in proliferation in culture nor in nude mice from wild-type HT 29 cells.

In a second study attempting to determine the phenotypic effects of wild-type c-Src over-expression on human colon cancer cells, c-Src-transfected KM12C colon cancer cells expressing up to fold more c-Src than wild-type cells were injected subcutaneously and intrasplenically into nude mice Irby et al. Cells with a higher level of c-Src expression formed more rapidly growing tumors than did wild-type cells, but did not form liver metastases. Interestingly, transfected and wild-type cells grown in vitro showed similar proliferation rates.

These two studies indicate that, first, the level of Src and its activity alters the rate of tumor growth proportionally in vivo , and, second, growth rates in vitro do not necessarily reflect the growth rates of cells in vivo. This suggests that tumor cell growth is greatly influenced by the microenvironment, and perhaps indicates the potential for Src activity in the tumor cell to affect the expression of tumor promoting proteins by the host. These studies also demonstrate that over-expression of wild-type c-Src alone, while clearly affecting tumor growth in vivo , may be insufficient to induce the metastatic phenotype.

Src activity has recently been studied in pancreatic cancer. Lutz et al. Kinase activity was only detectable in cancer cells and this activity did not correlate with either the c-Src or Csk protein levels. Further studies using the tyrosine kinase inhibitor, herbimycin A, indicated that the Src activity was instrumental in promoting the growth of pancreatic tumor cells. One method by which Src increases pancreatic tumor growth was suggested by Flossmann-Kast et al. This group found that Src causes an increase in the number of insulin-like growth factor receptor IGF-R molecules per cell, thus enhancing IGF-dependent growth.

In a another study based on a rat model of pancreatic carcinogenesis Visser et al. This increase in activity was accompanied by a relocalization of c-Src protein to the nucleus, suggesting a role for Src in gene regulation. Src family kinases Lck, Lyn, and Fgr have similarly been shown to be activated during leukemic cell growth Abts et al.

The majority of the data supporting a role for Src as a potential oncogene in human cancer is derived from experiments utilizing v-Src protein or other activated forms of Src to induce cellular transformation, tumorigenicity, tumor progression, and metastasis.

The v- src gene, encoded by Rous sarcoma virus, was the first transmissible gene found to induce tumors. It was originally discovered by Peyton Rous in Rous, as a transmissible agent that would produce tumors in chickens. The protein product of this gene, v-Src, is a tyrosine kinase with a cellular homolog, c-Src, which is found in normal cells and presumed to be a proto-oncogene Czernilofsky et al.

The structure of the two proteins is similar, but the regulatory carboxyl terminus of v-Src is truncated resulting in activation and numerous differences in amino acid sequence throughout the protein exist enhancing the activation Jove and Hanafusa, While the two proteins perform the same function, the kinase activity of v-Src and its capacity to transform are much higher than c-Src.

Moreover, cellular transformation by v-Src has been reported to produce a fold elevation in protein phosphotyrosine over that produced by c-Src. Despite relatively modest protein expression levels in cells, v-Src invariably results in high levels of cellular transformation as distinguished by altered cellular morphology, cytoskeletal reorganization, proliferation under low serum conditions, and anchorage independent growth.

The end result of these changes in vitro is the enhanced tumorigenicity in vivo. The phosphorylation of numerous cellular substrates on tyrosine residues by v-Src is likely responsible for the effects on cellular transformation. These phosphorylation events are presumed to affect proteins which regulate cell growth and differentiation and include, among others, transcription factors, members of signal transduction cascades, and growth factor receptors Brown and Cooper, ; Thomas and Brugge, Because oncogenes may, in some cases, represent fetal genes inappropriately expressed in adult tissues, further evidence for Src's role as an oncogene is derived from observations suggesting that it is involved in differentiation of fetal tissues.

This is especially true in neural tissues Bjelfman et al. Similar events occur in tumors of neuronal origin Bjelfman et al. An overproduction of c-Src by itself, however, is, at best, minimally transforming, suggesting that increased Src activity may play more of a role in tumor progression than in tumorigenesis Biscardi et al.

Until recently, the genetic evidence for Src as a human oncogene has been lacking. While numerous mutant forms of avian v-Src have been identified and multiple chicken c-Src mutants have been constructed, none have been previously observed in humans.

The recent observation that an activating mutation Src exists in a small subset of advanced human colon cancers with high Src activity lends credence to the hypothesis that Src may have oncogeneic potential Irby et al. Src was shown to induce cellular transformation, and augment tumor growth and metastatic potential in fibroblasts.

While elevation of Src protein levels is apparently common to a large number of cancers, this elevation is often modest when compared to the fold-increases of Src kinase activity that have been observed. These data suggest the relative importance of Src activation in human tumor development and progression. Several possible explanations exist for the activation of Src kinase in cancer. These receptors have been known to be active in the progression of cancer, and, in turn, may activate Src.

It has been suggested that the association between c-Src and these receptor tyrosine kinases is instrumental in malignant transformation Luttrell et al. A second possibility is that Src is activated post-translationally. Several modes of post-translational activation exist: insufficient Csk activity, increased activity of Src phosphatases, or interaction with viral or cellular proteins. Csk activity inactivates the human Src protein by phosphorylation of the negative regulatory tyrosine avian Tyr A decrease in the level of Csk protein or production of a defective Csk would permit a more active form of Src.

While studies of pancreatic carcinomas show no correlation between Src activity levels and Csk levels Lutz et al. Although this mode of activation is anticipated, it does not account for all of the activated Src kinase in human tumors. Studies of human breast cancer cell lines demonstrated cells with elevated Src kinase activity, with or without increased Src protein levels.

A set of these breast cancer cells displayed active phosphatases that are believed to activate the Src by dephosphorylating the regulatory Tyr Egan et al. The mouse models of mammary carcinoma indicated above are examples of post-translational modification by cellular or viral proteins. Phosphorylation of Tyr upregulates the enzyme while phosphorylation of Tyr in the C-terminal tail by Csk renders the enzyme less active.

Similarly, they are activated at mitosis and play a role in cellular division at the G 2 -M transition phase. It is the responsibility of our customers to check the necessity of application of REACH Authorisation, and any other relevant authorisations, for their intended uses. Publishing research using ab? Please let us know so that we can cite the reference in this datasheet.

There are currently no Customer reviews or Questions for ab Please use the links above to contact us or submit feedback about this product. Your name Your email. Send me a copy of this email. I agree to the terms and conditions. Non-receptor protein tyrosine kinase that plays pivotal roles in numerous cellular processes such as proliferation, migration, and transformation.

In concert with PTK2B, plays an important role in osteoclastic bone resorption. Once it is recruited to the activated integrins, by PTK2B, it phosphorylates CBL which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase.

Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. Contains 1 protein kinase domain.