I

MAPKAPK-1 Elk-1 SAP-1a

Figure 4 Activation of the Ras-Raf-MAPK pathway. Upon cell stimulation with EGF, the EGFR recruits Grb2 that in turn will engage mSoS, the Ras-specific GEF protein (left panel). The GTP-bound Ras protein will then recruit effector molecules such as Raf kinase, subsequent activation of the MAPK cascade down to transcription factors Elk-1 and SAP-1a (right panel).

Growth factors

Figure 5 The PI3K pathway. This simplified scheme represent the molecular events leading to PKB phosphorylation and activation, and the subsequent activation of its downstream effectors.

inositol ring to generate the second messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). PKB and its upstream activating kinase PDK1 are then recruited at the plasma membrane, an event accomplished by direct interaction between its PH domains and the generated PtdIns(3,4,5)P3 molecules. Colocalization of PDK1 at the plasma membrane allows the phosphorylation of Thr308 in the activation loop by this enzyme, which is necessary and sufficient for PKB activation.293,294 However, maximal enzymatic activation of PKB requires phosphorylation of Ser473, a residue located in its C-terminal regulatory domain.295 The molecular identity(ies) of the kinase(s) responsible for the phosphorylation of the Ser473 residue, often refered as PDK2, is still controversial and has been hypothesized, among other proteins, to be DNA-PK 296,297 or the mTOR/rictor complex.298

The activated PKB phosphorylates and modulates the function of important regulators of cell proliferation (e.g., p21Cip1, p27Kip1), survival (e.g., Bad, caspase 9, CREB), and metabolism (e.g., GSK3b). As a direct consequence of this broad spectrum of activities,299 the biological consequences of uncontrolled PI3K-PKB activation in cancer cells are critical in inhibiting apoptosis and in promoting tumor cell growth, proliferation and angiogenesis.

Activation of the PI3K-PKB pathway in tumor cells is accomplished by various mechanisms that reflect the importance of this signaling cascade in the biology of human cancers. In addition to persistent recruitment and activation of PI3K by deregulated RPTKs (e.g., erbB-2), it has been reported that one of the catalytic subunits of PI3K (the catalytic p110asubunit of class IA PI3Ks) is amplified and overexpressed in tumors. Moreover, activating mutations in PIK3CA300-304 have been identified in different types of cancers: 74 of 199 colorectal cancers (32%), 4 of 15 glioblastomas (27%), 3 of 12 gastric cancers (25%), 1 of 12 breast cancers (8%), and 1 of 24 lung cancers (4%). Other biological alterations can also affect the correct regulation of the PtdIns(3,4,5)P3 signal transducer.305 Loss of the dual-specificity phosphatase and tensin (PTEN) homolog deleted on chromosome 10, which modulates the activation state of the pathway by removing the 3'-phosphate group from PtdIns(3,4,5)P3, has been found in a large fraction of advanced human cancers,306-310 including glioblastomas, endometrial, breast, thyroid, and prostate cancers, and melanoma. Germline mutation of PTEN also results in autosomal dominant cancer syndromes such as Cowden disease, a heritable cancer risk syndrome, and several related conditions (e.g., Bannayan-Riley-Ruvalcaba syndrome or Proteus syndrome). In addition to the preceding alterations, PKB isoforms have been found to be amplified or overexpressed to different degrees in various human tumors, including ovarian, breast, prostate, and pancreatic cancers.311-313

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