Evo Devo

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cellular survival

To die or not to die, that is the question ...

Cellular survival is partly a matter of avoiding apoptosis, and is dependent on specific signaling cascades. Induction of programmed cell death (apoptosis) is a highly regulated process that can be suppressed by a variety of extracellular stimuli, including the various growth factors. The survival-stimulating capacity of trophic factors is attributable, at least in part, to the phosphatidylinositide 3'-OH kinase (PI3K)/c-Akt kinase cascade.

: Akt : c-akt : MEKs : MEK1 : PDK1 : phosphatidylinositide-3-OH kinase : 3-phosphoinositide-dependent protein kinase-1 : PI3K : thymoma viral proto-oncogene : v-akt :

Akt1 is 'thymoma viral proto-oncogene 1', a synonym for protein kinase B, and is a serine/threonine kinase that promotes cellular survival. Proto-oncogenes participate in a variety of normal cellular functions, but have the potential to tranform into cellular oncogenes when mutated. Proto-oncogenes normally function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation. Cellular proto-oncogenes resident in transforming retroviruses are designated as c- (cellular origin) as opposed to v- (retroviral origin).

When activated, Akt exerts anti-apoptosis effects through phosphorylation of substrates that directly regulate the apoptosis machinery (Bad or caspase 9), or phosphorylation of substrates that indirectly inhibit apoptosis (human telomerase reverse transcriptase subunit (hTERT), forkhead transcription family members, or IkB kinases). Akt promotes survival in vitro when cells are exposed to different apoptotic stimuli such as growth factor deprivation, UV irradiation, matrix detachment, cell cycle discordance, DNA damage, and administration of anti-Fas antibody, TGF-β, glutamate, or bile acids.

Akt is the cellular homologue of the product of the v-akt oncogene and has 3 isoforms, Akt1, 2, and 3 (or PKB-α, -β, and -γ). Akt is activated by many growth factors, including IGF-I, EGF, βFGF, insulin, interleukin-3, interleukin-6, heregulin, and VEGF. Full activity of all three isoforms requires phosphorylation of both a site in the activation domain and another site in the C-terminal hydrophobic motif. Akt1 activation requires PDK1 phosphorylation of T308 in the activation domain and is dependent on the products of phosphatidylinositol (PI) 3-kinase (PI3-K), phosphatidylinositol 3,4 bisphosphate (PIP2) and phosphatidylinositol 3,4,5 trisphosphate (PIP3). Cellular levels of PIP2 and PIP3 are controlled by the tumor suppressor, dual-phosphatase PTEN, which dephosphorylates PIP2 and PIP3 at the 3' position.[2]

The phosphatidylinositide-3-OH kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways play central roles in the regulation of cell survival and proliferation. Pyruvate dehydrogenase kinase, isoenzyme 1 or 3-phosphoinositide-dependent kinase-1 (PDK1) contains an amino-terminal kinase domain and a carboxyl-terminal pleckstrin homology (PH) domain. PDK1 appears to be conserved throughout evolution (27-31). Although the PDK1 PH domain binds the lipid products of the phosphatidylinositol 3-kinase (PI3K) reaction, binding of these lipids does not alter PDK1 activity, rather it is necessary to localize PDK1 to the plasma membrane. Sphingosine, another biologically active lipid, activates PDK1 toward a variety of substrates (26). It is well established that PDK1 phosphorylates the activation loop (kinase subdomain VIII) of AGC kinase family members p70S6 kinase, Akt, protein kinase A (cAMP-dependent protein kinase), various protein kinase C (PKC) isoforms, and serum- and glucocorticoid-inducible kinases (26, 31, 33-37).(fft-s)

PDK1 promotes MAPK activation in a MEK-dependent manner, and the direct targets of PDK1 in the MAPK pathway are the upstream MAPK kinases MEK1 and MEK2. PDK1 phosphorylation sites in MEK1 and MEK2 are Ser222 and Ser[2][2][6], respectively, and are known to be essential for full activation. PDK1 is associated with maintaining the steady-state phosphorylated MEK level and cell growth. [s] MEK-1 is a dual threonine and tyrosine recognition kinase that phosphorylates and activates mitogen-activated protein kinase (MAPK). MEK-1 is in turn activated by phosphorylation.[1]

Agonist stimulation of phosphatidylinositide 3-kinase (PI 3-kinase) activates a pathway that leads to activation of ADP-ribosylation factor (ARF) 6, which regulates plasma membrane trafficking and cortical actin formation by cycling between inactive GDP and active GTP-bound conformations.

Phosphatidylinositide-3' (PI 3)-kinase participates in Kit-ligand (KL)-induced adhesion of bone marrow-derived mast cells (BMMCs) to fibronectin. The Kit receptor tyrosine kinase is a member of the PDGF receptor subfamily that mediates diverse responses including proliferation, survival, chemotaxis, migration, differentiation, and adhesion to extracellular matrix. PKCs play a dual role as both positive and negative regulators of Kit function by acting as downstream mediators in addition to participating in a negative feedback loop that down-regulates Kit receptor activity. PKC is activated by diacylgylcerol and by products of PI-3 kinase. Kit participates in the secretion of inflammatory mediators in connective tissue mast cells. Receptor-proximal PI 3-kinase activation and activation of a PKC isoform appear to have a role in Kit-mediated secretory enhancement, adhesion, and cytoskeletal reorganization.[r]

Regulation of TopBP1 oligomerization by Akt/PKB for cell survival.
Regulation of E2F1-mediated apoptosis is essential for proper cellular growth. This control requires TopBP1, a BRCT (BRCA1 carboxyl-terminal) domain-containing protein, which interacts with E2F1 but not other E2Fs and represses its proapoptotic activity. We now show that the regulation of E2F1 by TopBP1 involves the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, and is independent of pocket proteins. Akt phosphorylates TopBP1 in vitro and in vivo. Phosphorylation by Akt induces oligomerization of TopBP1 through its seventh and eighth BRCT domains. The Akt-dependent oligomerization is crucial for TopBP1 to interact with and repress E2F1. Akt phosphorylation is also required for interaction between TopBP1 and Miz1 or HPV16 E2, and repression of Miz1 transcriptional activity, suggesting a general role for TopBP1 oligomerization in the control of transcription factors. Together, this study defines a novel pathway involving PI3K-Akt-TopBP1 for specific control of E2F1 apoptosis, in parallel with cyclin-CDK-Rb for general control of E2F activities. Liu K, Paik JC, Wang B, Lin FT,
Lin WC. Regulation of TopBP1 oligomerization by Akt/PKB for cell survival. EMBO J. 2006 Sep 28; [Epub ahead of print]

Regulation of E2F1 by BRCT domain-containing protein TopBP1. [Mol Cell Biol. 2003] PMID: 12697828
TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival. [Genes Dev. 2004] PMID: 15075294
Phosphatidylinositol 3-kinase/Akt positively regulates Fas (CD95)-mediated apoptosis in epidermal Cl41 cells. [J Immunol. 2006] PMID: 16709838
Transcriptional repression by RB-E2F and regulation of anchorage-independent survival. [Mol Cell Biol. 2001] PMID: 11313458
Specificity in the activation and control of transcription factor E2F-dependent apoptosis. [Proc Natl Acad Sci U S A. 2003] PMID: 12954980
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: Akt : c-akt : PDK1 : phosphatidylinositide-3-OH kinase : 3-phosphoinositide-dependent protein kinase-1 : PI3K : thymoma viral proto-oncogene : v-akt :


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