Protein kinases are enzymes within cells that act by attaching phosphate groups to the amino acid residues of various proteins. This process of phosphorylation serves two primary roles: as a molecular on-off switch to trigger a cascade of cellular events and as a “connector” that binds proteins to each other. Therefore, protein kinases play a primary role in the complex signaling systems that transfer information between and within cells. They are generally classified into two groups:
A. Based on their specificity for target amino acids:
– Serine- or threonine-specific kinases— Catalyze the phosphorylation of groups on serine and threonine residues
– Tyrosine-specific kinases— Catalyze the phosphorylation of tyrosine residues
– Mixed function kinases— Catalyze serine, threonine, or tyrosine phosphorylation
A. Based on their specificity for target amino acids:
– Serine- or threonine-specific kinases— Catalyze the phosphorylation of groups on serine and threonine residues
– Tyrosine-specific kinases— Catalyze the phosphorylation of tyrosine residues
– Mixed function kinases— Catalyze serine, threonine, or tyrosine phosphorylation
B. Based on their structure and cellular localization:
– Receptor kinases— Defined by a hydrophobic transmembrane domain that passes through the plasma membrane, an extracellular ligand-binding domain, and a cytoplasmically located kinase domain. The extracellular ligand-binding domain is typically glycosylated and conveys ligand specificity.
The three main families are
– Receptor kinases— Defined by a hydrophobic transmembrane domain that passes through the plasma membrane, an extracellular ligand-binding domain, and a cytoplasmically located kinase domain. The extracellular ligand-binding domain is typically glycosylated and conveys ligand specificity.
The three main families are
- erbB (HER)
- platelet-derived growth factor receptor (PDGFR)
- vascular endothelial growth factor receptor (VEGFR).
–> Other well-known receptors include IGF-1R, KIT, and mutant FLt-3 receptors.
– Nonreceptor kinases— Unlike the receptor kinases, these agents have no transmembrane or extracellular domains and may be associated with the cytoplasmic surfaces by membrane localization via a lipid modifi-cation that anchors them to the phospholipid bilayer or by noncovalent binding to a membrane receptor. Examples include the ABL, JAK, FAK, and SRC kinases.
– Nonreceptor kinases— Unlike the receptor kinases, these agents have no transmembrane or extracellular domains and may be associated with the cytoplasmic surfaces by membrane localization via a lipid modifi-cation that anchors them to the phospholipid bilayer or by noncovalent binding to a membrane receptor. Examples include the ABL, JAK, FAK, and SRC kinases.
FUNCTIONS OF PROTEIN KINASES
The function of protein kinases is to provide a mechanism for transmitting information from a factor outside a cell to the interior of the cell without the initiating factor having to cross the cell membrane. For example, growth factors and polypeptide hormones in the extracellular milieu can exert a regulatory effect on cells by activating specific gene transcription in the nucleus of target cells without passing through their cyto-plasmic membranes. By this mechanism, protein kinases help regulate cellular func-tions such as proliferation, cell-matrix adhesion, cell-cell adhesion, movement, apoptosis control, transcription, and membrane transport
The function of protein kinases is to provide a mechanism for transmitting information from a factor outside a cell to the interior of the cell without the initiating factor having to cross the cell membrane. For example, growth factors and polypeptide hormones in the extracellular milieu can exert a regulatory effect on cells by activating specific gene transcription in the nucleus of target cells without passing through their cyto-plasmic membranes. By this mechanism, protein kinases help regulate cellular func-tions such as proliferation, cell-matrix adhesion, cell-cell adhesion, movement, apoptosis control, transcription, and membrane transport
ROLE OF PROTEIN KINASES IN CANCER
Protein kinases can play major etiologic roles in the initiation of malignancy and may contribute to the uncontrolled proliferation of cancer cells, tumor progression, and the development of metastatic disease. It is thought that cancer cells depend almost entirely on signaling by protein kinases for their continued proliferation, whereas normal cells rarely invoke these pathways.
Protein kinases can be altered in two main ways in tumor cells as described below.
Protein kinases can be altered in two main ways in tumor cells as described below.
- Mutations in Protein Kinases
A number of examples in which specific kinases have become mutated in cancer cells are known. For example, a mutation of the protein kinase ABL (i.e., BCR-ABL) is the etiologic agent in CML. The cytoplasmic tyrosine kinase BCR-ABL, which is constitutively active, is present in 15% to 30% of cases of adult acute lymphoblastic leukemia (ALL) and virtually all cases of CML. This mutation has been put to good use in the design of imatinib (kinase inhibitor). A second example can be found in patients with multiple endocrine neoplasia (type 2), in which mutations in RET tyrosine kinase may be responsible for development of the disease. Finally, EGFR mutations with enhanced kinase activity have been detected in several human tumor types.
- Overexpression of Protein Kinases
Expression of EGFR and its associated primary ligands epidermal growth factor (EGF) and transforming growth factor α(TGF-α) has been studied in several human malignancies with coexpression of EGFR and EGF observed to have both prognostic significance and a possible role in the pathogenesis of several human cancers. Specifically, overexpression of EGFR and EGF in several tumor types significantly reduces patient prognosis.
For example, members of the EGFR kinase family (EGFR, ErbB-2, HER2/neu, ErbB-3, and ErbB-4) are known to be overexpressed in some types of breast tumors. The HER2/neu RTK has been found to be amplified up to 100 times in the tumor cells of approximately 30% of cancer patients with invasive breast disease, and its presence is also associated with poor prognosis. Similarly, over expression of PDGF and PDGFR has been reported in meningioma, melanoma, and neuroendocrine cancers as well as tumors of the ovary, pancreas, stomach, lung, and prostate. Elevated levels of SRC kinase activity have also been noted in colon cancer specimens, implying that over expression may also be important in this disease.
Source : chemistry and pharmacology of anti cancer drugs 5.2 kinase inhibitors page 96
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For example, members of the EGFR kinase family (EGFR, ErbB-2, HER2/neu, ErbB-3, and ErbB-4) are known to be overexpressed in some types of breast tumors. The HER2/neu RTK has been found to be amplified up to 100 times in the tumor cells of approximately 30% of cancer patients with invasive breast disease, and its presence is also associated with poor prognosis. Similarly, over expression of PDGF and PDGFR has been reported in meningioma, melanoma, and neuroendocrine cancers as well as tumors of the ovary, pancreas, stomach, lung, and prostate. Elevated levels of SRC kinase activity have also been noted in colon cancer specimens, implying that over expression may also be important in this disease.
Source : chemistry and pharmacology of anti cancer drugs 5.2 kinase inhibitors page 96
hope it helped you
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