Trends in Cell Biology
ReviewsDirect targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction
Section snippets
EEA1: a PtdIns(3)P-binding protein in endosomal traffic
In budding yeast, PI 3-kinase plays an essential role in membrane traffic through the production of PtdIns(3)P (Ref. [4]). This 3′-phosphoinositide is also the most abundant product of PI 3-kinase activity in mammalian cells1, 15, 16, exceeding the combined levels of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 by approximately tenfold. Furthermore, PtdIns(3)P is present both in resting and growth-factor-stimulated cells, suggesting that, as in budding yeast, PtdIns(3)P might be the PI 3-kinase product
GRP1 and α-centaurin: two PtdIns(3,4,5)P3-binding proteins potentially involved in membrane traffic
In mammalian cells, wortmannin induces a rapid and striking alteration in the morphology of endosomes. This involves the appearance of tubular structures, which, in some cases, form an interconnected network, and enlarged perinuclear endosomes[15]. Another fungal toxin, brefeldin A (BFA) causes a similar morphological transformation[30]. An important difference between the effects of wortmannin and those of BFA is that BFA induces tubulation in membranes of both the secretory and endocytic
PDK-1, PKB and Tec kinases: PtdIns(3,4,5)P3-binding proteins in signal transduction
The generation of PtdIns(3,4,5)P3 and PtdIns(3,4)P2 by mammalian cells occurs almost exclusively as a response to hormones, growth factors and other extracellular stimuli. Thus, these higher-phosphorylated phosphoinositides are intrinsic parts of signal-transduction pathways, and their production leads to the wide diversity of responses elicited by such stimuli. One mechanism by which the transient generation of only two 3′-phosphoinositides can lead to a multiplicity of cellular responses is
Functional interdependency of trafficking and signalling pathways
The action of PI 3-kinase products to recruit proteins that function in cell signalling and membrane trafficking raises the possibility that the activity of signalling proteins might be regulated not only by their intrinsic catalytic activity and their recruitment to specific membrane domains, but also by the ensuing traffic of such membrane regions. The combination of signalling and trafficking events might determine the ultimate cellular response to a particular stimulus.
There are already
Future prospects
These considerations raise important unresolved issues for future work. Outstanding questions include the nature of the molecular mechanisms by which the multiple types of PI 3-kinases localize the synthesis of 3′-phosphoinositides in cells, the identities of additional effector proteins that bind to these lipids, and the modes by which such effectors coordinate downstream events. It is likely that the answers to these questions will cause further convergence of our conceptions about signal
Acknowledgements
We thank all the members of the Corvera and Czech laboratories whose work has contributed to the ideas presented in this review.
References (58)
Cell
(1989)Trends Biochem. Sci.
(1997)Cell
(1992)J. Biol. Chem.
(1996)J. Biol. Chem.
(1995)J. Biol. Chem.
(1994)J. Biol. Chem.
(1995)J. Biol. Chem.
(1996)- et al.
Mol. Cell
(1998) - et al.
Curr. Biol.
(1998)
Cell
Cell
Curr. Biol.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
FEBS Lett.
Curr. Opin. Cell Biol.
Cell
J. Biol. Chem.
Curr. Opin. Cell Biol.
Science
Proc. Natl. Acad. Sci. U. S. A.
Science
EMBO J.
Nature
Mol. Biol. Cell
Proc. Natl. Acad. Sci. U. S. A.
Cancer Res.
Cited by (185)
mTOR: Role in cancer, metastasis and drug resistance
2019, Seminars in Cancer BiologyCitation Excerpt :This activity is antagonized by PTEN (phosphatase and tensin homolog deleted on chromosome 10), the tumor suppressor which reverses the PIP3 to PIP2 [30]. Accumulation of the PIP3, the intracellular second messenger, at the plasma membrane recruits the protein serine-threonine kinases, Akt (a cellular homolog of the murine thymoma virus Akt8 oncogene), SGK1 (serum and glucocorticoid-induced kinase 1), and PDK1/2 (3-phosphatidylinositol dependent kinase-1 and 2), the PH (pleckstrin-homology) domain-containing proteins to the membrane [31] where, PDK1 phosphorylates Akt at threonine 308 that results in the activation of Akt and its signaling pathway [32]. Further, increased protein synthesis and cell proliferation signals from Akt reach the GTPase-activating protein TSC1/2 (tuberous sclerosis complex1/2) and active Akt directly phosphorylates that results in inactivation of TSC2 (known also as tuberin), which makes an enhanced Rheb (Ras homolog enriched in brain) activity [33].
Methods to measure the enzymatic activity of PI3Ks
2014, Methods in EnzymologyGenetic deregulation of the PIK3CA oncogene in oral cancer
2013, Cancer LettersMicrotubule network is required for insulin-induced signal transduction and actin remodeling
2013, Molecular and Cellular EndocrinologyTRIM50 protein regulates vesicular trafficking for acid secretion in gastric parietal cells
2012, Journal of Biological ChemistryVertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo
2011, Journal of Investigative Dermatology