Oncogenic signaling of class I PI3K isoforms

Denley, Adam; Kang, Seung Goo; Kärst, Uwe; Vogt, Peter K.

doi:10.1038/sj.onc.1210918

Cited by 97 publications

(94 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In colorectal cancers, PIK3CG was initially proposed to function as a tumor-suppressor gene (40), a finding disputed by a subsequent study (41). An oncogenic potential was then described for p110g, similarly to other class I A PI3K isoforms (42,43). A recent study described a critical role for p110g in pancreatic cancer, and hypothesized that PI3K/p110gamma overexpression is a key event in the disease progression (44).…”

Section: Discussionmentioning

confidence: 98%

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Guerreiro

Fattet

Kulesza

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110g (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110g phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma. Mol Cancer Res; 9(7); 925-35. '2011 AACR.

show abstract

Section: Discussionmentioning

confidence: 98%

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

Guerreiro

Fattet

Kulesza

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Further support for the importance of membrane binding on the activity of PI3K␣ is provided by genetically engineered forms of p110␣. When a myristylation site is engineered into p110␣, its resultant constitutive membrane binding activates Akt and other downstream targets in a pattern identical to that of the His1047Arg mutant (31)(32)(33). Similarly, fusion proteins in which WT p110␣ is joined to retroviral Gag sequences render the enzyme constitutively active by virtue of the membrane address supplied by the Gag domain (31,32).…”

Section: Discussionmentioning

confidence: 99%

“…When a myristylation site is engineered into p110␣, its resultant constitutive membrane binding activates Akt and other downstream targets in a pattern identical to that of the His1047Arg mutant (31)(32)(33). Similarly, fusion proteins in which WT p110␣ is joined to retroviral Gag sequences render the enzyme constitutively active by virtue of the membrane address supplied by the Gag domain (31,32). Finally, the oncogenic transforming activity of the myristylated or Gagfusion forms of p110␣ is identical to that of the naturally occurring His1047Arg mutant in the absence of membrane tags (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane

Mandelker

Gabelli²,

Schmidt‐Kittler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

271

383

View full text Add to dashboard Cite

Mutations in oncogenes often promote tumorigenesis by changing the conformation of the encoded proteins, thereby altering enzymatic activity. The PIK3CA oncogene, which encodes p110␣, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3K␣), is one of the two most frequently mutated oncogenes in human cancers. We report the structure of the most common mutant of p110␣ in complex with two interacting domains of its regulatory partner (p85␣), both free and bound to an inhibitor (wortmannin). The N-terminal SH2 (nSH2) domain of p85␣ is shown to form a scaffold for the entire enzyme complex, strategically positioned to communicate extrinsic signals from phosphopeptides to three distinct regions of p110␣. Moreover, we found that Arg-1047 points toward the cell membrane, perpendicular to the orientation of His-1047 in the WT enzyme. Surprisingly, two loops of the kinase domain that contact the cell membrane shift conformation in the oncogenic mutant. Biochemical assays revealed that the enzymatic activity of the p110␣ His1047Arg mutant is differentially regulated by lipid membrane composition. These structural and biochemical data suggest a previously undescribed mechanism for mutational activation of a kinase that involves perturbation of its interaction with the cellular membrane.

show abstract

“…The isoform-specific inhibitors for p110β, p110γ, and p110δ have been described in a previous publication (45). The specific inhibitor A66 for p110α was synthesized and characterized as described previously (compound 6) (46).…”

Section: Methodsmentioning

confidence: 99%

Cancer-derived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110α

Sun

Hillmann

Hofmann

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

143

120

View full text Add to dashboard Cite

Cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (Nterminal SH2) domains of p85α, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function. They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85α. The mutant proteins are still able to bind to the catalytic subunits p110α and p110β. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110α, and p110α is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85α and p110α while preserving the stabilizing interaction between p85α iSH2 and the adapter-binding domain of p110α.oncogenic transformation | target of rapamycin T he phosphoinositide 3-kinase (PI3K) signaling pathway is deregulated in most human cancers by differential gene expression, amplification, or mutation. Of particular interest are mutations that occur in the catalytic subunit p110α of class I PI3K, because they confer a strong gain of function upon the enzyme, resulting in enhanced catalytic activity, constitutive signaling, and oncogenicity in vitro and in vivo (1-8). There have also been early reports of cancer-specific mutations in p85α, a regulatory subunit of class I PI3K (9-14). Such mutations gained high significance by recent comprehensive genomic analyses of glioblastomas (15,16). Approximately 9% of these tumors harbor a mutation in p85α. The mutations cluster in the inter-SH2 (iSH2) domain of p85α, involving residues that interact with the C2 domain of the catalytic subunit p110α (15,17). The iSH2-C2 domain interaction has an inhibitory effect on enzyme activity, and the mutations in the iSH2 domain of p85α could weaken this interaction and release the inhibition of PI3K activity (15,(17)(18)(19). A similar mechanism has been proposed for the gain-of-function mutations in the helical domain of p110α that alleviate an inhibitory interaction with the N-terminal SH2 domain (nSH2) of p85α (20).We have studied mutations in p85α (referred to as p85). Most of these were identified in a genomic characterization of glioblastoma (15) and map to the iSH2 domain of p85; one was an engineered mutation that maps to the nSH2 domain of p85. These mutations show oncogenic potency in cell culture and elevated levels of downstream signaling and operate through the p110α isoform of the catalytic subunit of class I PI3K. Our observations extend recent studies of the p85α mutants using different cell systems (17,19) by providing quantitative data on the oncogenic potency of the mutations and by presenting evidence that suggests a unique role of p110α for the p85 mutation-induced gain of function in PI3K activity. ResultsCancer-Derived Mutations of p85 Induce Oncogenic Transform...

show abstract

Oncogenic signaling of class I PI3K isoforms

Cited by 97 publications

References 76 publications

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane

Cancer-derived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110α

Contact Info

Product

Resources

About