Constitutive Signaling by Aberrant PI3K in Cancer

Stable Identifier
R-HSA-2219530
Type
Pathway
Species
Homo sapiens
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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
18079394 The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations

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

Science 2007
21478295 PIK3R1 (p85?) is somatically mutated at high frequency in primary endometrial cancer

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

Cancer Res. 2011
19962665 Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation

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

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

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

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

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

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

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

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

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

Proc. Natl. Acad. Sci. U.S.A. 2010
Participants
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Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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