Abstract
The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP 3), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP3 as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP3 generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1391-1396 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 108 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jan 25 2011 |
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Keywords
- Cancer
- Signal transduction
ASJC Scopus subject areas
- General
Cite this
Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB. / Maag, David; Maxwell, Micah; Hardesty, Douglas A.; Boucher, Katie L.; Choudhari, Namrata; Hanno, Adam G.; Ma, Jenny F.; Snowman, Adele M; Pietropaoli, Joseph W.; Xu, Risheng; Storm, Phillip B.; Saiardi, Adolfo; Snyder, Solomon H; Resnick, Adam C.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 4, 25.01.2011, p. 1391-1396.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB
AU - Maag, David
AU - Maxwell, Micah
AU - Hardesty, Douglas A.
AU - Boucher, Katie L.
AU - Choudhari, Namrata
AU - Hanno, Adam G.
AU - Ma, Jenny F.
AU - Snowman, Adele M
AU - Pietropaoli, Joseph W.
AU - Xu, Risheng
AU - Storm, Phillip B.
AU - Saiardi, Adolfo
AU - Snyder, Solomon H
AU - Resnick, Adam C.
PY - 2011/1/25
Y1 - 2011/1/25
N2 - The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP 3), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP3 as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP3 generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.
AB - The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP 3), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP3 as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP3 generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.
KW - Cancer
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=79951885087&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79951885087&partnerID=8YFLogxK
U2 - 10.1073/pnas.1017831108
DO - 10.1073/pnas.1017831108
M3 - Article
C2 - 21220345
AN - SCOPUS:79951885087
VL - 108
SP - 1391
EP - 1396
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 4
ER -