Tyrosine Kinase - Function


The term kinase describes a large family of enzymes that are responsible for catalyzing the transfer of a phosphoryl group from a nucleoside triphosphate donor, such as ATP, to an acceptor molecule. Tyrosine kinases catalyze the phosphorylation of tyrosine residues in proteins. The phosphorylation of tyrosine residues in turn causes a change in the function of the protein that they are contained in.

Phosphorylation at tyrosine residues controls a wide range of properties in proteins such as enzyme activity, subcellular localization, and interaction between molecules. Furthermore tyrosine kinases function in many signal transduction cascades wherein extracellular signals are transmitted through the cell membrane to the cytoplasm and often to the nucleus where gene expression may be modified. Finally mutations can cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer.

Tyrosine kinases function in a variety of processes, pathways, and actions, and are responsible for key events in the body. The receptor tyrosine kinases function in transmembrane signaling, whereas tyrosine kinases within the cell function in signal transduction to the nucleus. Tyrosine kinase activity in the nucleus involves cell-cycle control and properties of transcription factors. In this way, in fact, tyrosine kinase activity is involved in mitogenesis, or the induction of mitosis in a cell; proteins in the cytosol and proteins in the nucleus are phosphorylated at tyrosine residues during this process. Cellular growth and reproduction may rely in some part on tyrosine kinase. Tyrosine kinase function has been observed in the nuclear matrix, which is comprised not of chromatin, but of the nuclear envelope and a “fibrous web” that serves to physically stabilize DNA. More specifically, Lyn, a type of kinase in the Src family that was identified in the nuclear matrix, appears to control the cell cycle. Src family tyrosine kinases are closely related, but demonstrate a wide variety of functionality. Roles or expressions of Src family tyrosine kinases vary significantly according to cell type, as well as during cell growth and differentiation. Lyn and Src family tyrosine kinases in general have been known to function in signal transduction pathways. There is evidence that Lyn is localized at the cell membrane; Lyn is associated both physically and functionally with a variety of receptor molecules.

Fibroblasts – a type of cell that synthesizes the extracellular matrix and collagen and is involved in wound healing – that have been transformed by the polyomavirus possess higher tyrosine activity in the cellular matrix. Furthermore, tyrosine kinase activity has been determined to be correlated to cellular transformation. It has also been demonstrated that phosphorylation of a middle-T antigen on tyrosine is also associated with cell transformation, a change that is similar to cellular growth or reproduction.

The transmission of mechanical force and regulatory signals are quite fundamental in the normal survival of a living organism. Protein tyrosine kinase plays a role in this task, too. A protein tyrosine kinase called pp125 is likely at hand in the influence of cellular focal adhesions, as indicated by an immunofluorescent localization of the said kinase. Focal adhesions are macromolecular structures that function in the transmission of mechanical force and regulatory signals. Among the scientific community, pp125 is also referred to as FAK (focal adhesion kinase), due to its aforementioned presence in cellular focal adhesions. The protein tyrosine kinase pp125 is one of the major phosphotyrosine–containing proteins in unaffected (untransformed) avian and rodent fibroblast cells (fibroblast cells are explained above in some detail). Fibroblasts are a cell type responsible for wound healing and cell structure in animals, among a number of other relatively minor but important jobs that take place often or occasionally. The sequence and structure of pp125, when compared to National Biomedical Research Foundation and GenBank data bases, may be quite unique, meaning it could be a new member of the protein tyrosine kinase family. This protein tyrosine kinase is up to about 70% unique compared to some other protein tyrosine kinases, a figure that is unlike those between actual members of an established protein tyrosine kinase family. Also, the amino acid sequence that was observed indirectly signifies that it is associated with the cytoplasm, dubbing it one in a large group of cytoplasmic protein tyrosine kinases. It was discovered when monoclonal antibodies were observed to recognize it. Monoclonal antibodies, from chicken embryo cells transformed by pp60v-src, recognize seven different phosphotyrosine-containing proteins. One of these monoclonal antibodies, named 2A7, recognizes pp125, support for the idea that pp125 is, in fact, a protein tyrosine kinase.

Cellular proliferation, as explained in some detail above, may rely in some part on tyrosine kinase. Tyrosine kinase function has been observed in the nuclear matrix. Lyn, the type of kinase that was the first to be discovered in the nuclear matrix, is part of Src family of tyrosine kinases, which can be contained in the nucleus of differentiating, calcium-provoked kertinocytes. Lyn, in the nuclear matrix, among the nuclear envelope and the “fibrous web” that physically stabilizes DNA, was found functioning in association with the matrix. Also, it appeared to be conditional to cell cycle. The contribution of the Lyn protein to the total tyrosine kinase activity within the nuclear matrix is unknown, however; because the Lyn was extracted only partially, an accurate measurement of its activity could not be managed. Indications, as such, are that, according to Vegesna et al. (1996), Lyn polypeptides are associated with tyrosine kinase activity in the nuclear matrix. The extracted Lyn was enzymatically active, offering support for this notion.

Yet another possible and probable role of protein tyrosine kinase is that in the event of circulatory failure and organ dysfunction caused by endotoxin in rats, where the effects of inhibitors tyrphostin and genistein are involved with protein tyrosine kinase. As has become clear among many people, tyrosine kinase can be involved in some unfortunate things.

Tyrosine kinase is also involved in signaling. Signals in the surroundings received by receptors in the membranes of cells are transmitted into the cell cytoplasm. Transmembrane signaling due to receptor tyrosine kinases, according to Bae et al. (2009), relies heavily on interactions, for example, mediated by the SH2 protein domain; it has been determined via experimentation that the SH2 protein domain selectivity is functional in mediating cellular processes involving tyrosine kinase. Receptor tyrosine kinases may, by this method, influence growth factor receptor signaling. This is one of the more fundamental cellular communication functions metazoans.

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