Egf

FIGURE 11.1 Schematic depiction of receptor-mediated signaling in response to EGF binding to EGFR, highlighting the complexity of parallel pathways transmitting signals for growth, gene transcription, and survival, which are then mediated by effectors within the nucleus. See Plate 11.1 in Color Plate Section.

FIGURE 11.1 Schematic depiction of receptor-mediated signaling in response to EGF binding to EGFR, highlighting the complexity of parallel pathways transmitting signals for growth, gene transcription, and survival, which are then mediated by effectors within the nucleus. See Plate 11.1 in Color Plate Section.

terminus of Sos [67-70]. The exchange factors facilitate activation of the Ras family of guanine nucleotide triphosphatases by exchanging GDP for GTP. To promote this process, Sos binds to GDP-Ras, which leads to dissociation of GDP, allowing GTP to bind to the Ras-Sos complex. Sos then dissociates, leaving Ras in its active GTP-bound form. Excessive activation of these pathways has been implicated in the development of a variety of human tumors. In certain tumor types, mutation of one of the ras genes to a constitutively active protein has been associated with tumorigenesis [71]. Although such mutations are rare in gliomas [72,73], Ras activity is nonetheless markedly elevated [73-75] as a result of deregulation of upstream signaling elements, such as growth factor receptors [76].

In addition to promoting activation of Ras via the Grb2-Sos pathway, receptor tyrosine kinases activate a number of parallel signaling pathways by interactions between phosphotyrosine domains and SH2 domains of other cytoplasmic intermediates (Fig. 11.1). For example, PLCy^and PI3K, which play critical roles in phospholipid metabolism, are recruited to the activated receptor by adapter proteins, such as Gab1 [77]. PI3K stimulates inositol phosphorylation that in turn leads to activation of Akt, which has multiple functions, among which are cell survival. Activation of PLCy^produces other important lipid intermediates, such as diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). IP3 leads to release of intracellular calcium, thereby activating calmodulin-dependent protein kinases. The calcium, in combination with DAG, also activates protein kinase C (PKC), which then stimulates many of the same downstream elements that are activated by Ras [78-80]. PKC, in particular, appears to also activate Ras directly, and by employing a mechanism that is distinct from the aforementioned Grb2-Sos interaction [78,81], provides an additional pathway by which receptor-mediated mitogenic signaling can stimulate downstream proliferative and cell survival cascades.

Receptors that lack tyrosine kinase activity but contain sites for tyrosine phosphorylation may become transactivated by association with a soluble tyrosine kinase, such as a member of the Src family [82]. Following phosphorylation, these proteins can interact with adapter proteins, such as Shc, to activate G-protein-mediated signaling pathways and can also directly stimulate downstream effectors. Finally, both PDGFR and EGFR have also been found to activate members of the signal transducers and activators of transcription (STAT) family, which translocate to the nucleus to directly influence the transcription of genes involved in cell cycle progression and cell survival [83-88].

Signal Transduction

MAPK Cascade

Following activation of the membrane-associated components of the various signaling pathways, downstream signals reach the nucleus by a variety of mechanisms (Fig. 11.1). One of the most critical pathways involves the mitogen-activated protein kinase (MAPK) cascade. This cascade involves at least three separate protein kinases. The most proximal kinase in the cascade is the Raf (MAPKKK) family, which includes at least three members. Raf, a serine/threonine kinase, is the cellular homolog of a viral oncogene, capable of inducing transformation if constitutively overexpressed. Raf is recruited to the cell membrane, stabilized by interaction with other proteins, such as members of the 14-3-3 family, and possibly by dimerization [89,90], and phosphorylated to an active form. Activated Raf phosphorylates and activates MAP/ERK kinase (MEK, also known as MAPKK), a dual-specificity (tyrosine and serine/ threonine) kinase, which subsequently activates MAPK (also known as ERK (extracellular signalregulated kinase)) by phosphorylating tyrosine and threonine residues [91-93]. MAPKs are serine/threo-nine kinases that activate a number of additional cytoplasmic downstream mediators that regulate transcription, protein translation, and cytoskeletal rearrangement. These cytoplasmic mediators include other kinases, such as p-90RSK (ribosomal S6kinase) and p70-S6 kinase, which are broadly grouped as MAPK-activated protein kinases (MAPKAPKs), proteins that can impact directly on the nucleus by activating transcription regulatory factors, such as Fos, Jun, Myc, and Elk-1 [94-96]. In addition, these proteins can directly stimulate translation by activating ribosomal S6 protein, or down-regulate transcription by activating GSK3 (glycogen synthase kinase 3).

In parallel with the MAPK pathway, which transmits signals for cell growth and proliferation, are other similar pathways that convey signals that respond to injury or stress [97,98]. These include the JNK (Jun terminal kinase) pathway, which may be activated directly or indirectly via receptor tyrosine kinase signaling via Ras-related G-proteins, such as Rac, followed by activation of PAK (p21Ras-related protein activated kinase), which activates a MAPKKK molecule. This in turn activates the dual specificity

EGFR amplification/overexpression in glioma progression

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