Rbd

Figure 3.3.3.B. Mutations in PIK3CA. Mutations in the catalytic subunit of Phosphatidylinositol 3-Kinase. The arrowheads indicate the location of missense mutations, and boxes represent functional domains. They include the P85-binding domain, the RAS-binding domain, the C2 domain, the helical domain, and the kinase domain. The percentage of mutations detected within each region is indicated below, and the fraction of tumors with mutations is noted above. [Reproduced from Samuels-Lev et al. 2004. With permission.]

Figure 3.3.3.B. Mutations in PIK3CA. Mutations in the catalytic subunit of Phosphatidylinositol 3-Kinase. The arrowheads indicate the location of missense mutations, and boxes represent functional domains. They include the P85-binding domain, the RAS-binding domain, the C2 domain, the helical domain, and the kinase domain. The percentage of mutations detected within each region is indicated below, and the fraction of tumors with mutations is noted above. [Reproduced from Samuels-Lev et al. 2004. With permission.]

in exon 5, which encodes the phosphatase catalytic core motif, and recurrent mutations also arise at CpG dinucleotides implying mutations induced by deamination. Hot spot mutations on CpG islands are R233X, R235X, and R335X. The G129E mutation in the catalytic domain of PTEN, which disrupts the lipid phosphatase activity, but does not affect PTEN's ability to dephosphorylate protein targets, is specifically associated with Cowden syndrome patients. Hence, the loss of lipid phosphatase activity is sufficient to cause increased susceptibility to cancer. Because the G129E mutant is also defective in mediating G1 arrest, the lipid phosphatase activity is needed to inhibit cell cycle progression.

• In primary non-small cell lung carcinomata, DJ-1 expression is often increased compared to the surrounding nonneoplastic lung tissue, and correlates positively with relapse incidence [Kim et al. 2005]. DJ-1 is also overexpressed in breast and prostate cancer. This leads to increased activity of the PKB signaling pathway.

• Mutations in the lkb1 gene cause Peutz-Jeghers syndrome, a disorder associated with multiple gastrointestinal hamartomatous polyps and a 15-fold increased risk of developing cancer. The lack of LKB1 activity allows enhanced signaling through mTOR.

• Tuberous sclerosis occurs based on inherited loss-of-function mutations in the genes tsc-1 or tsc-2. It predisposes to hamartomata in multiple organs, including the brain, skin and kidneys. tsc-1 (hamartin) [van Slegtenhorst et al. 1997] has 23 exons, 21 of which are coding. The transcript is 8.5 kb long and encodes for a 1,164 amino acid transmembrane protein. TSC-1 forms a complex with TSC-2, with both being important in the prevention of hamartomata.

3.3.4 The JAK/STAT pathway

JAK Kinases (Janus Kinases, JAKs) are universally required for signal transduction from cytokine receptors. Because cytokine receptors do not have intrinsic tyrosine kinase activity JAKs serve as the receptor-associated tyrosine kinases. Cytokine receptor ligation and dimerization recruits two molecules of JAKs, which then bind to two molecules of Signal Transducer and Activation of Transcription (STAT) proteins, leading to their dimerization. Interferon signaling is mediated by the JAK/STAT pathway. Similarly, the ligation of receptor tyrosine kinases, such as the EGF Receptor, recruits JAK and SRC, which phosphorylate and activate two molecules of STAT, inducing their dimerization.

There are four JAK proteins, JAK-1 {1p31.3}, JAK-2 {9p24}, JAK-3 {19p13.1}, and TYK-2 {19p13.2}. Upon receptor ligation, JAKs create the STAT docking sites by autophosphorylating and phosphorylating the cytoplasmic receptor domain. The downstream targets of JAK Kinases, the STAT proteins [Schindler et al. 1992; Fu et al. 1992] are critical in mediating virtually all cytokine signaling (Figure 3.3.4.A). This pathway transmits information directly from transmembrane receptors to target gene promoters, without the involvement of second messengers. There are seven known STATs, -1, -2, -3, -4, -5A, -5B, and -6 (Figure 3.3.4.B). In the absence of receptor activation, STATs are localized in the cytoplasm. Upon receptor ligation, they are recruited to the cytoplasmic tail through SH2 domains on STAT and phosphotyrosine moieties on the receptor. These interactions are highly specific and determine the selectivity of receptor mediated STAT activation. The tyrosine phosphorylation of STATs leads to their homodimerization and heterodimerization through domains. STAT dimers are rapidly transported to the nucleus. STATs also undergo acetylation of lysine 685 by Histone Acetyl Transferases, which is essential for the formation of stable dimers. Most STATs recognize an inverted repeat element with the consensus sequence TTX46AA (g-interferon activating sequence, GAS element). Dimers of STATs induce the transcription of genes for growth promoting or apoptosis preventing effectors, including bcl-X, cyclin D1, and c-myc. The nonreceptor tyrosine kinases SRC and ABL may cause STAT phosphorylation and activation. JAK-2 or the RAC1 GTPase may bind to and mediate STAT3 activity.

MYC is a target transcription factor in the JAK/STAT pathway. The family of genes that encode the MYC proteins (c-MYC, N-MYC, L-MYC) generates transcription factors of the basic helix-loop-helix zipper family. The 64 kD protein MYC consists of an NH2-terminal transcriptional activation domain, DNA binding and dimerization domains, and a binding site for the heterologous dimerization partner protein MAX, with which it forms an active complex. Because MAX contains basic helix-loop-helix and leucine zipper domains, but lacks the transactivation domain present in c-MYC, MYC-MAX dimerization is necessary for

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