Constitutive Signaling by Aberrant PI3K in Cancer

Stable Identifier
R-HSA-2219530
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Constitutive Signaling by Aberrant PI3K in Cancer
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Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011).
Literature References
PubMed ID Title Journal Year
21478295 PIK3R1 (p85?) is somatically mutated at high frequency in primary endometrial cancer

Urick, ME, Rudd, ML, Godwin, AK, Sgroi, D, Bell, DW, Merino, M

Cancer Res. 2011
18079394 The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations

Samuels, Y, Mandelker, D, Schmidt-Kittler, O, Kinzler, KW, Vogelstein, B, Amzel, LM, Gabelli, SB, Velculescu, VE, Huang, CH

Science 2007
19962665 Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation

Yue, P, Kaminker, JS, Kan, Z, Modrusan, Z, Dbouk, HA, Kenski, DM, Stinson, J, Waring, P, Janakiraman, V, Stern, HM, Wang, W, Jaiswal, BS, Lorenzo, M, Peters, BA, Seshagiri, S, Chaudhuri, S, Eby, M, Bowman, KK, Wu, J, Kljavin, NM, Dela Vega, T, Backer, JM, de Sauvage, FJ, Li, H

Cancer Cell 2009
17626883 Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit

Inbar, Y, Miled, N, Hon, WC, Williams, RL, Yan, Y, Backer, JM, Zvelebil, M, Wolfson, HJ, Schneidman-Duhovny, D, Perisic, O

Science 2007
20009532 Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS

Zhao, L, Vogt, PK

Cell Cycle 2010
18317450 Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells

Stocking, C, Bäsecke, J, Bergholz, U, Trümper, L, Horn, S, McCubrey, JA, Jücker, M

Oncogene 2008
16339315 The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells

Liu, Z, Shin, E, Roberts, TM, Wang, L, Loda, MF, Zhao, JJ

Proc. Natl. Acad. Sci. U.S.A. 2005
20713702 Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha

Hofmann, BT, Hillmann, P, Vogt, PK, Sun, M, Hart, JR

Proc. Natl. Acad. Sci. U.S.A. 2010
Participants
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as an event of
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cross References
BioModels Database
Authored
Orlic-Milacic, M  (2012-07-18)
Reviewed
Zhao, JJ  (2012-08-13)
Yuzugullu, H  (2012-08-13)
Thorpe, L  (2012-08-13)
Created
Orlic-Milacic, M  (2012-05-01)
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