Signal Transduction and Cancer

Cancer is a complex family of diseases characterized by host of cells that have acquired a malignant phenotype, rendering them more genetically unstable and less responsive to external stimuli and their own environment. In a landmark paper, Hanahan and Weinberg have described six 'hallmarks of cancer' that collectively lead to malignant growth5: self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion/metastasis. One common underlying mechanism that can operate in many of these areas is aberrant intracellular signal transduction, brought about by the increased genetic instability of the cell.6 There are numerous examples where upregulation, or constitutive activation, of key signaling pathways allows the cell to proliferate in the absence of extracellular mitogenic signals7'8 or where downregulation of a death-signaling pathway allows the cell to evade apoptosis.9

For primary neoplasia to develop into carcinoma, cellular invasion into adjacent tissue through the basement membrane is necessary, followed by vascularization of the growing tumor mass.10 Invasion and metastasis result from changes in intracellular signaling pathways, which allow the cell to become insensitive to the normal regulatory effects of cell-cell and cell-matrix contacts, and acquisition of a motile phenotype.11 Progression of a tumor beyond a certain size requires it to develop a new vasculature from the untransformed endothelial cells of the host. Endothelial cells do not typically acquire intracellular signaling defects, and angiogenesis is often driven through overexpression of extracellular growth factors.12

Many of the features of cancer cells described above are mediated through intracellular signal transduction pathways, and involve reversible protein phosphorylation13 (phosphorylation of nonproteins, such as lipids, can also mediate signal transduction,14 but this is not considered in this review). These pathways are critical for normal cells to function, but are often inappropriately activated in many tumors. Selective inhibition of such inappropriate signaling offers new treatment opportunities for cancer patients and the potential to find well-tolerated and effective drugs targeted at the specific molecular lesions that drive tumor cell growth.

7.08.2.2 Receptor Tyrosine Kinases (RTKs)

RTKs typically comprise an extracellular N-terminal ligand-binding domain (ECD) (often glycosylated), a hydrophobic transmembrane domain, an intracellular juxtamembrane domain (often autoinhibitory), and a cytoplasmic kinase domain containing multiple tyrosine residues capable of phosphorylation.15 Most RTKs are monomeric single-chain peptides in the unactivated form, although the Met/Ron family comprise a and b subunits (linked by disulfide bridges),16 and the insulin receptor family consists of two extracellular a chains disulfide-linked to two transmembrane b subunits.17 Ligand binding to the ECD causes receptor dimerization/oligomerization, which allows intracellular auto-and/or transphosphorylation within the newly formed signaling complex.18 Typically, homodimers are formed, although some kinases can form heterodimers, and these may include partners that do not bind external ligands (e.g., ErbB2)19 or which lack catalytic kinase activity (e.g., ErbB3).20 These signaling complexes may also include chaperone proteins (e.g., HSP90),21 which confer conformational stability and are essential for signal transduction. The resultant phosphotyrosine residues within the kinase signaling complex can recruit downstream signaling molecules that contain phosphotyrosine recognition elements such as SH2 or PTB domains.22,23 Some 30 families of RTKs have been described, on the basis of structural homology, and crystallographic data on 10 different RTK kinase domains have recently been reviewed.24

RTK ligand upregulation at both the RNA and protein level can result in uncontrolled proliferative drive, as can direct effects on kinase protein levels.25 In a small number of well-documented instances, germline mutations can result in the expression of activated kinase.26 However, activating somatic mutations are a much more significant cause of kinase activation in cancer, and can occur either through direct mutation in the kinase domain or via remote mutations that drive conformational change or limit the influence of internal regulatory domains or external regulatory proteins.27 A number of mechanisms for therapeutic intervention have been identified for RTKs; those that are common to cytoplasmic kinases will be discussed later. Inhibitors that target the extracellular domains of RTKs, such as antibodies, can block ligand-induced activation of the intracellular kinase domain.28 An alternative approach is the administration of an agent (typically a solubilized fragment of the extracellular domain of the kinase itself), which sequesters the ligand.29

7.08.2.3 Cytoplasmic and Nuclear Kinases

The majority of kinases are intracellular and do not have extracellular domains for ligand binding, although, as with RTKs, they can often localize to membranes (e.g., Fak)30 and form multimeric signaling complexes with other proteins (e.g., Aurora B).31 Cytoplasmic kinases are typically expressed in inactive forms that can be activated in a number of ways, including (auto)phosphorylation.32 Compounds such as imatinib (1) (see Figure 1) have been shown to bind preferentially to inactive forms of the kinase, preventing adoption of an inactive conformation and resulting in

TflKC

TflKC

What Neoplasia Tree Model Flow Chart

Figure 1 The human kinome.This phylogenetic tree depicts the relationships between members of the complete superfamily of human protein kinases. The main diagram illustrates the similarity between the protein sequences of these catalytic domains. Each kinase is at the tip of a branch, and the similarity between various kinases is inversely related to the distance between their positions on the tree diagram. Most kinases fal l into smal l fami l ies of highly related sequences, and most fami l ies are part of larger groups. The seven major groups are label ed and colored distinctly. Other kinases are shown in the center of the tree, colored gray. The inset diagram shows trees for seven atypical protein kinase families. These proteins have verified or strongly predicted kinase activity, but have little or no sequence similarity to members of the protein kinase superfamily. A further eight atypical protein kinases in small families of one or two genes are not shown. (Courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).)

Figure 1 The human kinome.This phylogenetic tree depicts the relationships between members of the complete superfamily of human protein kinases. The main diagram illustrates the similarity between the protein sequences of these catalytic domains. Each kinase is at the tip of a branch, and the similarity between various kinases is inversely related to the distance between their positions on the tree diagram. Most kinases fal l into smal l fami l ies of highly related sequences, and most fami l ies are part of larger groups. The seven major groups are label ed and colored distinctly. Other kinases are shown in the center of the tree, colored gray. The inset diagram shows trees for seven atypical protein kinase families. These proteins have verified or strongly predicted kinase activity, but have little or no sequence similarity to members of the protein kinase superfamily. A further eight atypical protein kinases in small families of one or two genes are not shown. (Courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).)

downregulation of the downstream signaling cascade.33 However, the most widely exploited mechanism of inhibition is to deliver compounds that target the ATP-binding site in the activated kinase.34'35 Even here, it is possible to subdivide compounds into those that compete directly with ATP for the adenine-binding site, those that occupy an adjacent site (e.g., the 'selectivity pocket'), and those inhibitors that, by virtue of a chemically reactive moiety, compete with ATP for its binding site, but bind irreversibly. Thus, gefitinib (27) and erlotinib (28) (see Figure 6) are epidermal growth factor receptor (EGFR) inhibitors that compete reversibly with ATP for the adenine-binding site within the hinge region,36,37 while CI-1033 (31) (see Figure 7) is an irreversible EGFR inhibitor that forms a covalent interaction with a specific cysteine residue within the hinge region.38 In contrast, the MEK (mitogen-activated protein (MAP) kinase/ extracellular signal-related kinase kinase) inhibitor CI-1040 (78) (see Figure 15) occupies an allosteric site adjacent to the ATP-binding site.39

Compounds that target substrate binding can also be identified,40 and inhibitors of p38 kinase, which seem to target the binding site used by regulatory proteins, have also been described recently.41 Both mechanisms are potentially attractive as they may offer ways of improving kinase selectivity. Nature has a clear need to regulate kinase activity, and a variety of phosphatases42 and other regulatory proteins have evolved to this purpose, including many well-established tumor-suppressors such as phosphatase and tensin homologue deleted on chromosome ten (PTEN), which is lost in b 50% of human tumors.43

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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