Cinderella finds her shoe: The first Vps34 inhibitor uncovers a new PI3K-AGC protein kinase connection

Biochemical Journal

Volumn 464, Issue 2, 2014, Pages e7-e10

  Bilanges, Benoit ^a   Vanhaesebroeck, Bart ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Autophagy; Endosome; Phosphoinositide 3 kinase (PI3K); Phox homology (PX) domain; PtdIns(3)P; Serum and glucocorticoid regulated protein kinase 3 (SGK3); Vacuolar protein sorting 34 (Vps34) inhibitor

Indexed keywords

AGC PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE; PROTEIN SERINE THREONINE KINASE; SERUM AND GLUCOCORTICOID REGULATED KINASE 1; SERUM AND GLUCOCORTICOID REGULATED KINASE 2; SERUM AND GLUCOCORTICOID REGULATED KINASE 3; UNCLASSIFIED DRUG; 1-((2-((2-CHLOROPYRIDIN-4YL)AMINO)-4'-(CYCLOPROPYLMETHYL)-(4,5'-BIPYRIMIDIN)-2'-YL)AMINO)-2-METHYLPROPAN-2-OL; AMINOPYRIDINE DERIVATIVE; IMMEDIATE EARLY PROTEIN; PHOSPHATIDYLINOSITOL; PYRIMIDINE DERIVATIVE; SERUM-GLUCOCORTICOID REGULATED KINASE; SGK3 PROTEIN, HUMAN;

CATALYSIS; CELL STIMULATION; CELLULAR DISTRIBUTION; CLINICAL TRIAL (TOPIC); DOWN REGULATION; DRUG POTENCY; ENZYME ACTIVE SITE; GENE FUNCTION; MUTATIONAL ANALYSIS; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; ANTAGONISTS AND INHIBITORS; AUTOPHAGY; CHEMISTRY; ENDOSOME; GENETICS; HUMAN; METABOLISM; PHOSPHORYLATION; PROTEIN TRANSPORT;

CINDERELLA;

AMINOPYRIDINES; AUTOPHAGY; CLASS III PHOSPHATIDYLINOSITOL 3-KINASES; ENDOSOMES; HUMANS; IMMEDIATE-EARLY PROTEINS; PHOSPHATIDYLINOSITOLS; PHOSPHORYLATION; PROTEIN TRANSPORT; PROTEIN-SERINE-THREONINE KINASES; PYRIMIDINES;

EID: 84911935926     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20141218     Document Type: Review

References (14)

1. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. and Bilanges, B. (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol. 11, 329-341 CrossRef PubMed
2. Rodon, J., Dienstmann, R., Serra, V. and Tabernero, J. (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat. Rev. Clin. Oncol. 10, 143-153 CrossRef PubMed
3. Backer, J. M. (2008) The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem. J. 410, 1-17 CrossRef PubMed
4. Balla, T. (2013) Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol. Rev. 93, 1019-1137 CrossRef PubMed
5. Miller, S., Tavshanjian, B., Oleksy, A., Perisic, O., Houseman, B. T., Shokat, K. M. and Williams, R. L. (2010) Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327, 1638-1642 CrossRef PubMed
6. Miller, S., Oleksy, A., Perisic, O. and Williams, R. L. (2010) Finding a fitting shoe for Cinderella: searching for an autophagy inhibitor. Autophagy 6, 805-807 CrossRef PubMed
7. Bago, R., Malik, N., Munson, M. J., Prescott, A. R., Davies, P., Sommer, E., Shpiro, N., Ward, R., Cross, D., Ganley, I. G. and Alessi, D. R. (2014) Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem. J. 463, 413-427 PubMed
8. Tessier, M. and Woodgett, J. R. (2006) Role of the Phox homology domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3. J. Biol. Chem. 281, 23978-23989 CrossRef PubMed
9. Pearce, L. R., Komander, D. and Alessi, D. R. (2010) The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11, 9-22 CrossRef PubMed
10. Virbasius, J. V., Song, X., Pomerleau, D. P., Zhan, Y., Zhou, G. W. and Czech, M. P. (2001) Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate. Proc. Natl. Acad. Sci. U.S.A. 98, 12908-12913 CrossRef PubMed
11. Dowdle, W. E., Nyfeler, B., Nagel, J., Elling, R. A., Liu, S., Triantafellow, E., Menon, S., Wang, Z., Honda, A., Pardee, G. et al. (2014) Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat. Cell Biol., doi:10.1038/ncb3053 PubMed
12. Ronan, B., Flamand, O., Vescovi, L., Dureuil, C., Durand, L., Fassy, F., Bachelot, M. F., Lamberton, A., Mathieu, M., Bertrand, T. et al. (2014) A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol., in the press
13. White, E. and DiPaola, R. S. (2009) The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 15, 5308-5316 CrossRef PubMed
14. Bruhn, M. A., Pearson, R. B., Hannan, R. D. and Sheppard, K. E. (2013) AKT-independent PI3-K signaling in cancer: emerging role for SGK3. Cancer Manag. Res. 5, 281-292 PubMed